EP2125723A1 - 6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (s1p) receptor antagonist biological activity - Google Patents

6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (s1p) receptor antagonist biological activity

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Publication number
EP2125723A1
EP2125723A1 EP08727502A EP08727502A EP2125723A1 EP 2125723 A1 EP2125723 A1 EP 2125723A1 EP 08727502 A EP08727502 A EP 08727502A EP 08727502 A EP08727502 A EP 08727502A EP 2125723 A1 EP2125723 A1 EP 2125723A1
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Prior art keywords
group
carbons
compound
carbon atoms
heterocyclic
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German (de)
English (en)
French (fr)
Inventor
Richard L. Beard
Haiqing Yuan
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Allergan Inc
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Allergan Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to derivatives and/or analogues of sphingosine and pharmaceutical compositions, including such derivatives and/or analogues, which are useful as drugs for the treatment of fungal infections, allergic diseases, immune disorders, etc.
  • Sphingosine is a compound having the chemical structure shown in the general formula described below, in which Y 1 is hydrogen. It is known that various sphingo lipids, having sphingosine as a constituent, are widely distributed in the living body including on the surface of cell membranes of cells in the nervous system.
  • a sphingolipid is one of the lipids having important roles in the living body.
  • a disease called lipidosis is caused by accumulation of a specified sphingolipid in the body.
  • Sphingolipids present on cell membranes function to regulate cell growth; participate in the development and differentiation of cells; function in nerves; are involved in the infection and malignancy of cells; etc. Many of the physiological roles of sphingolipids remain to be solved.
  • ceramide a derivative of sphingosine, has an important role in the mechanism of cell signal transduction has been indicated, and studies about its effect on apoptosis and cell cycle have been reported.
  • Sphingosine- 1 -phosphate is an important cellular metabolite, derived from ceramide that is synthesized de novo or as part of the sphingomeyeline cycle (in animals cells). It has also been found in insects, yeasts and plants.
  • the enzyme, ceramidase acts upon ceramides to release sphingosine, which is phosphorylated by spingosine kinase, a ubiquitous enzyme in the cytosol and endoplasmic reticulum, to form sphingosine- 1 -phosphate.
  • the reverse reaction can occur also by the action of sphingosine phosphatases, and the enzymes act in concert to control the cellular concentrations of the metabolite, which concentrations are always low. In plasma, such concentration can reach 0.2 to 0.9 ⁇ M, and the metabolite is found in association with the lipoproteins, especially the HDL.
  • sphingosine- 1 -phosphate formation is an essential step in the catabolism of sphingoid bases.
  • sphingosine- 1 -phosphate is a potent messenger molecule that perhaps uniquely operates both intra- and inter-cellularly, but with very different functions from ceramides and sphingosine.
  • the balance between these various sphingolipid metabolites may be important for health.
  • sphingosine- 1 -phosphate promotes cellular division (mitosis) as opposed to cell death (apoptosis), which it inhibits.
  • mitosis mitochondria division
  • apoptosis cell death
  • Intracellularly it also functions to regulate calcium mobilization and cell growth in response to a variety of extracellular stimuli.
  • sphingosine-1 -phosphate exerts many of its extra-cellular effects through interaction with five specific G protein-coupled receptors on cell surfaces. These are important for the growth of new blood vessels, vascular maturation, cardiac development and immunity, and for directed cell movement.
  • Sphingosine-1 phosphate is stored in relatively high concentrations in human platelets, which lack the enzymes responsible for its catabolism, and it is released into the blood stream upon activation of physiological stimuli, such as growth factors, cytokines, and receptor agonists and antigens. It may also have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular disease.
  • physiological stimuli such as growth factors, cytokines, and receptor agonists and antigens. It may also have a critical role in platelet aggregation and thrombosis and could aggravate cardiovascular disease.
  • the relatively high concentration of the metabolite in high-density lipoproteins (HDL) may have beneficial implications for atherogenesis.
  • sphingosine-1 -phosphate together with other lysolipids such as sphingosylphosphorylcholine and lysosulfatide, are responsible for the beneficial clinical effects of HDL by stimulating the production of the potent antiatherogenic signaling molecule nitric oxide by the vascular endothelium.
  • lysophosphatidic acid it is a marker for certain types of cancer, and there is evidence that its role in cell division or proliferation may have an influence on the development of cancers.
  • Fungi and plants have sphingolipids and the major sphingosine contained in these organisms has the formula described below. It is known that these lipids have important roles in the cell growth of fungi and plants, but details of the roles remain to be solved.
  • derivatives of sphingolipids and their related compounds exhibit a variety of biological activities through inhibition or stimulation of the metabolism pathways.
  • These compounds include inhibitors of protein kinase C, inducers of apoptosis, immuno-suppressive compounds, antifungal compounds, and the like. Substances having these biological activities are expected to be useful compounds for various diseases.
  • the present invention provides a derivative or analogue of sphingosine that is able to regulate the functions of sphingolipid, and pharmaceutical compositions comprising said derivative or analogue.
  • R 1 R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, straight or branched chain alkyl having 1 to 12 carbons, alkenyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6 carbons and 1 or 2 triple bonds, carbocyclic hydrocarbon groups having from 3 to 20 carbon atoms, heterocyclic groups having up to 20 carbon atoms and at least one of oxygen, nitrogen and/or sulfur in the ring, halo, C 1 to C 12 haloalkyl, hydroxyl, C 1 to C 12 alkoxy, C 3 to C 20 arylalkyloxy, C 1 to C 12 alkylcarbonyl, formyl, oxycarbonyl, carboxy, C 1 to C 12 alkyl carboxylate, C 1 to C 12 alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl, and sulfonyl groups;
  • X and X 1 are independently selected from the group consisting of NR 5 , O and S;
  • R 5 is hydrogen, an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons, phenyl or lower alkylphenyl;
  • Y is a carbocyclic aryl or heterocyclic aryl group wherein said carbocylic aryl comprises from 6 to
  • said heterocyclic aryl comprises from 2 to 20 carbon atoms and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and wherein said aryl may be bonded to A at any position;
  • Z is O or S;
  • n is 0 or an integer of from 1 to 5;
  • o is 0 or an integer of from 1 to 3 ;
  • p is 0 or an integer of from 1 to 3;
  • q is 0 or 1 ;
  • r is 0 or 1 ;
  • A, A 1 and A 2 are independently selected from the group consisting of
  • B is selected from the group consisting of hydrogen, OR 6 , COOR 7 ,
  • R 10 and R 1 ' are independently selected from the group consisting of
  • alkynyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6
  • R 12 and R 13 are independently selected from the group consisting of
  • alkynyl having 2 to 6 carbons and 1 or 2 double bonds, alkynyl having 2 to 6
  • R 9 and/or R 12 and R 13 together, can form a divalent carbon radical
  • R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 or R 13 may be substituted with one or more
  • B is not hydrogen; or B is a
  • carbocyclic hydrocarbon group having from 3 to 20 carbon atoms, or a
  • heterocyclic group having up to 20 carbon atoms and at least one of
  • carbocyclic or heterocyclic group B may be bonded to A 2 at any position
  • the aryl group is a carbocyclic aryl or heterocyclic aryl group wherein said carbocylic aryl comprises from 6 to 20 atoms and said heterocyclic aryl comprise from 2 to 20 carbon atoms and from 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and preferably said aryl group is selected from the group consisting of benzene, pyridine, pyrazine, pyridazine, pyrimidine, triazine, thiophene, furan, thiazole, thiadiazole, isothiazole, oxazole,oxadiazole, isooxazole, naphthalene, quinoline, tetralin, chroman, thiochroman, tetrahydroquinoline, dihydronaphthalene, tetrahydronaphthalen, chromene, thiochromene, dihydroquinoline, indan, dihydrobenzofuran
  • Said aryl groups can be bonded to the above moiety at any position.
  • Said aryl group may itself be substituted with any common organic functional group including but not limited to C 1 to C 12 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, halo, C 1 to C 12 haloalkyl, hydroxyl, C 1 to C 12 alkoxyl, C 1 to C 12 alkylcarbonyl, formyl, oxycarbonyl, carboxyl, C 1 to C 12 alkyl carboxylate, C 1 to C 12 alkyl amide, aminocarbonyl, amino, cyano, diazo, nitro, thio, sulfoxyl, or sulfonyl groups.
  • Z is O.
  • the carbocyclic aryl group will comprise from 6 to 14 carbon atoms, e.g. from 6 to 10 carbon atoms.
  • the heterocyclic aryl group will comprise from 2 to 14 carbon atoms and one or more, e.g. from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • A is CH 2 .
  • X is NH
  • n is 0 or an integer of 1 or 2 and R 4 is fluoro.
  • R 1 is i-propyl.
  • R 3 is selected from the group consisting of phenyl, which may be substituted with one or two flouro groups, and pyridyl.
  • p is 0.
  • a 1 and A 2 are absent.
  • B is OR 6 or COOR 7 .
  • X is O
  • r is 1
  • a 1 is absent
  • a 2 is (CH 2 ) V , wherein v is 1 or 2
  • B is OR 6 Or NR 8 R 9
  • R 6 , R 8 and R 9 are methyl.
  • B is CONR 8 R 9 wherein R 8 and R 9 are selected from the group consisting of H, methyl, ethyl and propyl, or R 8 and R 9 , together with N, form a 5-member ring.
  • R 8 and R 9 are selected from the group consisting of H, methyl, ethyl and propyl, or R 8 and R 9 , together with N, form a 5-member ring.
  • a 1 is absent, r is 0,
  • a 2 is CH 2 and B is OR 6 , wherein R 6 is H, or X is O, r is 1 and B is COR 10 ,wherein R 10 is methyl.
  • methyl 6-methoxyindole-2-carboxylate is treated with an electrophilic compound (e.g. benzyl bromide) in the presence of an weak base (e.g. potassium carbonate) to produce an N-alkylated indole (e.g. methyl 1- benzyl-6-methoxyindole-2-carboxylate).
  • an electrophilic compound e.g. benzyl bromide
  • an electrophilic compound e.g. benzyl bromide
  • an electrophilic compound e.g. potassium carbonate
  • the resulting 2-alkyl indole is carboxylated in the 3 -position by treatment with dimethylformamide and phosphorus oxychloride followed by sodium hypochlorite oxidation of the resulting aldehyde.
  • the carboxylic acid may be further functionalized by treatment with an amine in the presence of N- (3-dimethylaminopropyl)-N'-ethylcarbodimide (EDC) to produce a 6- methoxyindole-3-carboxamide derivative (e.g. 3,4-difluorophenylmethyl 6- methoxy-2-isopropyl-l-benzylindole-3-carboxamide).
  • the carboxylic acid may also be treated with an alcohol or thiol in the presence of EDC to produce an ester and thiol ester derivatives, respectively.
  • the 6-methoxy group may then be deprotected using boron tribromide and the resulting hydroxide subjected to alkylating (e.g. cyclopentyl iodide/potassium carbonate) or acylating (e.g. pivaloyl chloride/ pyridine) reagents to produce a large variety of 6-substituted indole homologs and derivatives within the scope of the invention.
  • alkylating e.g. cyclopentyl iodide/potassium carbonate
  • acylating e.g. pivaloyl chloride/ pyridine
  • ethyl 4-iodobenzoate may be nitrated in the 3- position with fuming nitric acid and the resulting nitro compound reduced under mild conditions (e.g. SnCl 2 -H 2 O) to produce ethyl 3-amino-4- iodobenzoate.
  • This compound may be converted to the indole by treatment with a terminal alkyne (e.g. 3-methylbutyne) in the presence of a palladium catalyst and copper iodide followed by heating the aryl alkyne in the presence copper iodide.
  • the resulting 2-alkyl indole may then be carbonylated in the 3 -position by treatment with dimethylformamide and phosphorus oxychloride and N- alkylated as described above (benzyl bromide, potassium carbonate), followed by sodium hypochlorite oxidation to produce an N-alkylindole-3 -carboxylic acid.
  • the carboxylic acid may be further functionalized by treatment with an amine in the presence of EDC to
  • 6-methoxyindole-3-carboxamide derivative e.g. 3-pyridylmethyl 1- benzyl-6-carboethoxy-2-isopropylindole-3-carboxamide.
  • the carboxylic acid may also be treated with an alcohol or thiol in the presence of EDC to produce an ester and thiol ester derivatives, respectively.
  • the 6-carboethoxy group may be further functionalized to produce a large variety of 6-substituted indole homo logs and derivatives within the scope of the invention.
  • the 6- carboethoxy group be hydrolyzed with strong base and the resulting carboxylic acid converted to the carboxylic acid chloride, which could be reacted with various alcohols or amines in the presence of base to produce ester or amide derivatives, respectively, such as 3-pyridylmethyll-benzyl-2-isopropyl-6-(l- pyrrolidinylcarbamoyl)indole-3-carboxamide.
  • the 6-carboethoxy group could be reduced to an alcohol and re-oxidized to an aldehyde intermediate, which may then be treated with an amine under reducing conditions to give amine derivatives such as 3-pyridylmethyl l-benzyl-2- isopropyl-6-(l-pyrrolidinylmethyl)-indole-3-carboxamide.
  • the aldehyde may also be treated with oxime or hydrazine compounds to produce oxime and hydrazone derivatives, respectively.
  • many compounds within the scope of the invention may be produced by the general route depicted in Scheme 2.
  • Me refers to methyl
  • tBu refers to t-butyl
  • iPr refers to i-propyl
  • Ph refers to phenyl
  • “Pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • “Alkyl” refers to a straight-chain, branched or cyclic saturated aliphatic hydrocarbon. Preferably, the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.
  • Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl and the like.
  • alkenyl refers to a straight-chain, branched or cyclic unsaturated hydrocarbon group containing at least one carbon—carbon double bond.
  • the alkenyl group has 2 to 12 carbons. More preferably it is a lower alkenyl of from 2 to 7 carbons, most preferably 2 to 4 carbons.
  • the alkenyl group may be optionally substituted with one or more substituents selected fpm the group consisting of hydroxyl, cyano, alkoxy, O, S, NO 2 , halogen, dimethyl amino and SH.
  • Alkynyl refers to a straight-chain, branched or cyclic unsaturated hydrocarbon containing at least one carbon—carbon triple bond.
  • the alkynyl group has 2 to 12 carbons. More preferably it is a lower alkynyl of from 2 to 7 carbons, most preferably 2 to 4 carbons.
  • the alkynyl group may be optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, alkoxy, O, S, NO 2 , halogen, dimethyl amino and SH.
  • Alkoxy refers to an “O-alkyl” group.
  • Aryl refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups.
  • the aryl group may be optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO 2 , amine, thioether, cyano, alkoxy, alkyl, and amino.
  • Alkaryl refers to an alkyl that is covalently joined to an aryl group. Preferably, the alkyl is a lower alkyl.
  • Aryloxy refers to an “O-aryl” group.
  • Arylalkyloxy refers to an “O-alkaryl” group.
  • Carbocyclic refers to cyclic saturated or unsaturated aliphatic hydrocarbon and aryl hydrocarbon groups wherein the ring atoms are exclusively carbons, and comprises from 6 to 20 carbon atoms, including said ring atoms.
  • Carbocyciic aryl refers to an aryl group w erein the ring atoms are canbo .
  • Heterocyclic refers to cyclic groups wherein the ring atoms comprise carbon atoms and at least one oxygen, nitrogen, and/or sulfur atom and may be saturated, unsaturated, i.e. have one or more double bonds, or aryl, and comprises up to 20 carbon atoms and from 1 to 5 of the above heteroatoms.
  • Heterocyclic aryl refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remainder of the ring atoms being carbon. Heteroatoms include oxygen, sulfur, and nitrogen.
  • Hydrocarbyl refers to a hydrocarbon radical having only carbon and hydrogen atoms.
  • the hydrocarbyl radical has from 1 to 20 carbon atoms, more preferably from 1 to 12 carbon atoms and most preferably from 1 to 7 carbon atoms.
  • Substituted hydrocarbyl refers to a hydrocarbyl radical wherein one or more, but not all, of the hydrogen and/or the carbon atoms are replaced by a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radical including a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g. fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, etc.
  • Amide refers to -C(O)-NH-R 1 , wherein R' is alkyl, aryl, alkylaryl or hydrogen.
  • Ester refers to -C(O)-O-R 1 , wherein R' is alkyl, aryl or alkylaryl.
  • Thioamide refers to -C(S)-NH-R', wherein R' is alkyl, aryl, alkylaryl or hydrogen.
  • Thiol ester refers to -C(O)-S-R', wherein R' is alkyl, aryl, alkylaryl or hydrogen.
  • “Amine” refers to a — N(R")R'" group, wherein R" and R" are independently selected from the group consisting of alkyl, aryl, and alkylaryl.
  • Thioether refers to -S-R", wherein R" is alkyl, aryl, or alkylaryl.
  • substituent on the phenyl moiety is referred to as an o, m or p substituent or a 2, 3 or 4 substituent, respectively.
  • substituent on the phenyl moiety is referred to as an o, m or p substituent or a 2, 3 or 4 substituent, respectively.
  • the 5 substituent is also a m substituent and the 6 substituent is an o substituent.
  • Specific compounds of the invention that are prepared according to Example 2 through 29 and/or Schemes 1 through 3, are able to inhibit the activity of sphingosine-1 -phosphate receptors reported in Table I, below.
  • Compounds were assessed for their ability to activate or block activation of the human S1P3 receptor in T24 cells stably expressing the human S1P3 receptor.
  • Ten thousand cells/well were plated into 384-well poly-D-lysine coated plates one day prior to use.
  • the growth media for the S1P3 receptor expressing cell line was McCoy's 5 A medium supplemented with 10% charcoal-treated fetal bovine serum (FBS), 1% antibiotic-antimycotic and 400 ⁇ g/ml geneticin.
  • the cells were washed twice with Hank's Balanced Salt Solution supplemented with 20 mM HEPES (HBSS/Hepes buffer). The cells were then dye loaded with 2 uM Fluo-4 diluted in the HBSS/Hepes buffer with 1.25 mM Probenecid and incubated at 37 0 C for 40 minutes. Extracellular dye was removed by washing the cell plates four times prior to placing the plates in the FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices). Ligands were diluted in HBSS/Hepes buffer and prepared in 384-well microplates.
  • Sphingosine-1 -Phosphate (SlP) was diluted in HBSS/Hepes buffer with 4 mg/ml fatty acid free bovine serum albumin.
  • the FLIPR transferred 12.5 ⁇ l from the ligand microplate to the cell plate and took fluorescent measurements for 75 seconds, taking readings every second, and then for 2.5 minutes, taking readings every 10 seconds. Drugs were tested over the concentration range of 0.61 nM to 10,000 nM. Data for Ca +2 responses were obtained in arbitrary fluorescence units and not translated into Ca + concentrations. IC 50 values were determined through a linear regression analysis using the Levenburg Marquardt algorithm.
  • the compounds of Table 1 B are prepared according to procedures analogous to the procedures of Schemes 1 through 3 and/or Examples 2 through 29. These compounds are also tested for ability to inhibit the activity of the S1P3 receptor.
  • Glaucoma As a result of the above activity of the compounds utilized in the method of the present invention, it is clear that such compounds may be used in treating the following diseases and conditions for the following reasons. Glaucoma
  • S1P3 subtypes are expressed in primary human trabecular meshwork cells and SlP decreases outflow facility >30% in perfused porcine eyes (See IOVS 45, 2263; 2004) by altering paracellular permeability. Dry Eye/Immunology
  • S1P3 receptor subtype is expressed in vascular endothelial cells and siRNA knockdown of S 1 P 1 and S 1 P3 inhibits angiogenesis. SlP also promotes vascular endothelial cell migration and promotes barrier assembly and integrity. Cardiovascular (S1P3)
  • mice lack SlP induced pulmonary edema.
  • KOH potassium hydroxide
  • K 2 CO 3 potassium carbonate
  • NaHCO 3 sodium bicarbonate
  • NaClO 2 sodium hypochlorite
  • LiAlH 4 lithium aluminum hydride
  • MOMCl methyl chloromethyl ether
  • NMO 4-methylmorpholine
  • Pd-C palladium on activated carbon
  • TPAP tetrapropylammonium perruthenate
  • Methyl 1-Benzyl-6-methoxy-1H-indole-2-carboxylate (Compound 2).
  • methyl 6-methoxy-1H-indole-2-carboxilate (Compound 1) 1.0 g, 4.9 mmol) in DMF (10 ml) was added K 2 CO 3 (2.0 g, 14.6 mmol) and benzyl bromide (0.87 ml, 7.3 mmol).
  • the mixture was stirred at room temperature for 40 h and was diluted with EtOAc, washed with H 2 O, brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by crystallization from Et 2 O to yield the title compound as an off-white solid.
  • Example 5 l-Benzyl-l-isopropyl-6-methoxy-1H-indole-3-carbaldehyde (Compound 5).
  • POCl 3 (0.48 ml, 5.23 mmol) was added dropwise to anhydrous DMF (2 ml) at 0 °C under argon. After stirred for 30 min, this solution was added dropwise to a solution of l-benzyl-2-isopropyl-6-methoxy-1H-indole (Compound 4, 583 mg, 2.09 mmol) in anhydrous DMF (8 ml) at 0 °C under argon.
  • Example 8 l-Benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3- carboxamide (Compound 8).
  • l-benzyl-N-(3,4- difluorobenzyl)-2-isopropyl-6-methoxy-1H-indole-3-carboxamide Compound 7, 452 mg, 1.0 mmol
  • CH 2 Cl 2 (20 ml) at 0 °C was added BBr 3 (1.0 M in CH 2 Cl 2 , 3.0 ml, 3.0 mmol) dropwise.
  • Example 9 l-benzyl-N-(3,4-difluorobenzyI)-6-ethoxy-2-isopropyl-1H-indole-3- carboxamide (Compound 9).
  • General Procedure A To a solution of 1- benzyl-N-(3 ,4-difluorobenzyl)-6-hydroxy-2-isopropyl- 1 H-indole-3 -carboxamide (Compound 8, 40 mg, 0.092 mmol) in DMF (2.0 ml) was added K 2 CO 3 (39 mg, 0.28 mmol) and iodoethane (22 ⁇ l, 0.28 mmol).
  • Example 11 l-Benzyl-N-(3,4-difluorobenzyl)-6-isopropoxy-2-isopropyl-1H-indoIe-3- carboxamide (Compound 11).
  • Example 12 l-Benzyl-6-butoxy-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3- carboxamide (Compound 12).
  • Example 13 l-Benzyl-N-(3,4-difluorobenzyl)-6-isobutoxy-2-isopropyl-1H-indole-3- carboxamide (Compound 13).
  • Example 15 l-BenzyI-6-(benzyloxy)-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3- carboxamide (Compound 15).
  • Example 16 l-Benzyl-6-(cyclopentoxy)-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3- carboxamide (Compound 16).
  • Example 17 l-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(2-methoxyethoxy)-1H- indole-3-carboxamide (Compound 17).
  • Example 19 l-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(tetrahydrofuran-3-yloxy)- 1H-indole-3-carboxamide (Compound 19).
  • Example 25 l-Benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indol-6-yl Isobutyrate (Compound 25).
  • Example 26 l-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(methoxymethoxy)-1H- indole-3-carboxamide (Compound 26).
  • Example 27 l-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-6-(tetrahydrofuran-2-yloxy)- 1H-indole-3-carboxamide (Compound 27).
  • Tetrahydrofuran-3-yl 4-methylbenzenesulfonate (Compound 28). To a solution of tetrahydrofuran-3-ol (500 mg, 5.67 mmol) in pyridine (10 ml) at 0 0 C was added 4-methylbenzene-l-sulfonyl chloride (1.08 g, 5.67 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na 2 SO 4 and concentrated in vacuo to yield crude oil (1-2 g).
  • Example 29 3-Iodotetrahydrofuran (Compound 29).
  • Crude 28 1.2 g, 4.96 mmol
  • dry acetone 50 ml
  • NaI 1.1 g, 7.44 mmol
  • the reacted was heated at 60 0 C for 2 days.
  • the mixture was diluted with water and extracted with diethyl ether.
  • the organic layer was washed with water, brine, dried over Na 2 SO 4 and concentrated in vacuo to yield crude oil which was used directly without purification.
  • the present invention includes a 6-substituted indole-3-carboxylic acid-N- arylmethyl amide having sphingosine-1 -phosphate antagonist activity wherein the 6-substituent is represented by the formula
  • a 2 is absent or is (CH 2 ) V , wherein v is 1 or 2;

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EP08727502A 2007-01-11 2008-01-10 6-substituted indole-3-carboxylic acid amide compounds having sphingosine-1-phosphate (s1p) receptor antagonist biological activity Withdrawn EP2125723A1 (en)

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EA201992707A1 (ru) 2013-11-18 2020-06-30 Глобал Блад Терапьютикс, Инк. Соединения и их применения для модуляции гемоглобина
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