WO2007039470A1 - 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives - Google Patents
4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives Download PDFInfo
- Publication number
- WO2007039470A1 WO2007039470A1 PCT/EP2006/066562 EP2006066562W WO2007039470A1 WO 2007039470 A1 WO2007039470 A1 WO 2007039470A1 EP 2006066562 W EP2006066562 W EP 2006066562W WO 2007039470 A1 WO2007039470 A1 WO 2007039470A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyrimidine
- carbonitrile
- phenyl
- alkyl
- trifluoromethylphenyl
- Prior art date
Links
- 0 *c1cccc(-c2nc(C#N)nc(N3CCNCC3)c2)c1 Chemical compound *c1cccc(-c2nc(C#N)nc(N3CCNCC3)c2)c1 0.000 description 2
- CKZICIVNPPIMGY-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1c1cc(-c2ccccc2)nc(C#N)n1)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1c1cc(-c2ccccc2)nc(C#N)n1)=O CKZICIVNPPIMGY-UHFFFAOYSA-N 0.000 description 1
- LGUFBRKFOLFDOJ-UHFFFAOYSA-N CC(C)(C1)N(C)CCN1c1cc(-c2cc(C(F)(F)F)ccc2)nc(C#N)n1 Chemical compound CC(C)(C1)N(C)CCN1c1cc(-c2cc(C(F)(F)F)ccc2)nc(C#N)n1 LGUFBRKFOLFDOJ-UHFFFAOYSA-N 0.000 description 1
- MBKGDSBGMIUXNH-UHFFFAOYSA-N CCN(CC)c1cc(-c2cc(C(F)(F)F)ccc2)nc(C#N)n1 Chemical compound CCN(CC)c1cc(-c2cc(C(F)(F)F)ccc2)nc(C#N)n1 MBKGDSBGMIUXNH-UHFFFAOYSA-N 0.000 description 1
- ATQOKTMDKTWZKG-UHFFFAOYSA-N CN(C)CCSc1cc(-c2cc(C(F)(F)F)ccc2)nc(C#N)n1 Chemical compound CN(C)CCSc1cc(-c2cc(C(F)(F)F)ccc2)nc(C#N)n1 ATQOKTMDKTWZKG-UHFFFAOYSA-N 0.000 description 1
- VSWNFVWHRRUHMM-UHFFFAOYSA-N Cc1nc(SC)nc(N)c1 Chemical compound Cc1nc(SC)nc(N)c1 VSWNFVWHRRUHMM-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N OC(C(F)(F)F)=O Chemical compound OC(C(F)(F)F)=O DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- 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
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- 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
- 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
- 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
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
-
- 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
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/38—One sulfur atom
-
- 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
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the invention relates to 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives, to pharmaceutical compositions comprising the same, as well as to the use of these derivatives for the preparation of a medicament for the treatment of cathepsin K related diseases such as osteoporosis and atherosclerosis.
- Cysteine proteases represent a class of peptidases characterised by the presence of a cysteine residue in the catalytic site of the enzyme, and these proteases are associated with the normal degradation and processing of proteins. Many pathological disorders or diseases are the results of abnormal activity of cysteine proteases such as over expression or enhanced activation.
- the cysteine cathepsins e.g. cathepsin B, K, L, S 1 V, F, are a class of lysosomal enzymes which are implicated in various disorders including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors, coronary disease, atherosclerosis, autoimmune diseases and infectious diseases.
- Cathepsin K has strong collagenolytic, elastase and gelatinase activities (Bromme et al., J. Biol, Chem, 271, 2126-2132, 1996) and is predominantly expressed in osteoclasts (Bromme and Okamoto, Biol. Chem. Hopp-Seyler, 376, 379-384, 1995). It cleaves key bone matrix proteins, including collagen type I and Il (Kaffienah et al., Biochem. J. 331 , 727-732, 1998), gelatine, osteopontin and osteonectin, and as such is involved in extracellular matrix metabolism necessary for normal bone growth and remodelling (Bossard et al., J. Biol. Chem.
- Cathepsin K inhibitors may therefore represent new therapeutic agents for the treatment of disease states in man such as osteoporosis.
- Inhibition of cathepsins K and/or S at sites of plaques prone to rupture may thus represent an effective way of preventing such events.
- Cathepsin S also has potent elastolytic (Arch. Biochem. Biophys., 299, 334-339, 1992; J. Biol. Chem., 267, 7258-7262, 1992) and collagenolytic activities (Biochem. J., 256, 433-440, 1998).
- Diseased human arteries overexpress both cathepsin K and S and exhibit a reciprocal deficiency of cystatin C, the most abundant endogenous inhibitor of cysteine proteases (J. Clin. Invest. 102, 576-583, 1998; J. Clin.
- Cathepsin S has been shown to be a key enzyme involved in invariant chain processing in human and mouse antigen-presenting cells (J. Clin. Invest. 110, 361- 369, 2002). This invariant chain processing regulates MHC class Il function and is associated with autoimmnune disorders. Saegusa et al (J. Clin. Invest. 110, 361-369, 2002) have thereafter demonstrated that inhibition of cathepsin S in vivo alters autoantigen presentation and development of organ-specific autoimmunity.
- 4-Amino-pyrimidine-2-carbonitrile derivatives have been disclosed as inhibitors of cathepsins K and/or S in the International Patent Application WO 03/020278 (Novartis Pharma GMBH), while structurally related 4-amino-pyrimidine-2 carbonitrile derivatives were recently disclosed in WO04/000819 (ASTRAZEN ECA AB) as Cathepsin S inhibitors.
- Pyrrolo-pyrimidines have likewise been disclosed as cathepsin K and/or S inhibitors in WO 03/020721 (Novartis Pharma GMBH) and WO 04/000843 (ASTRAZENECA AB). It has now been found that 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives having the general Formula I
- R represents 1-3 optional substituents independently selected from (Ci -4 )alkyl (optionally substituted with one or more halogens), (C 1-4 )alkyloxy (optionally substituted with one or more halogens) and halogen;
- X is NR 1 , O or S;
- R 1 is H or (C 1-4 )alkyl;
- Y is (C 1-4 )alkyl, benzyl or (C 2 - 6 )alkyl, substituted with a group selected from OH, (C 1-4 )alkyloxy, NR 2 R3, a 4-8 membered saturated heterocyclic ring comprising 1 or 2 heteroatoms selected from O, S and NR 4 , and a 5 or 6-membered aromatic heterocyclic group comprising 1-4 N atoms; or R 1 and Y form together with the nitrogen to which they are bonded a 5-8 membered saturated heterocyclic ring, optionally comprising a further heteroatom selected from O, S, NR 4 and NO; the ring being optionally substituted with NR 2 R3 or with 1 to 4 (C 1-3 )alkyl groups; R 2 and R 3 are independently H or (C 1-4 )alkyl; or R 2 and R 3 form together with the nitrogen to which they are bonded a 4-8 membered saturated heterocyclic ring, optionally comprising a further heteroatom selected
- R 4 is H, (Ci -6 )alkyl, (C 3-6 )cycloalkyl, (C 3-6 )cycloalkyl(C 1-4 )alkyl, (C 1-4 )alkyloxy(C 1-4 )alkyl, benzyl, amido(C 1-4 )alkyl, (C 1-6 )alkyloxycarbonyl(C 1-4 )alkyl or carboxy(C 1-4 )alkyl; or a pharmaceutically acceptable salt thereof, are inhibitors of cathepsin K and cathepsin S and can therefore be used for the preparation of a medicament for the treatment of cathepsin K and cathepsin S related disorders, e.g.
- (Ci -6 )alkyl as used in the definition of formula I, means a branched or unbranched alkyl group having 1-6 carbon atoms, like hexyl, pentyl, 3-methyl-butyl, butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.
- (Ci -4 )alkyl means a branched or unbranched alkyl group having 1-4 carbon atoms, like butyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl.
- the term (C 2- 6)alkyl, as used in the definition of Y of formula I, likewise means a branched or unbranched alkyl group having 2-6 carbon atoms, like hexyl, pentyl,, 3- methyl-butyl, butyl, isobutyl, tertiary butyl, propyl, isopropyl and ethyl.
- (C 3 _ 6 )cycloalkyl means a cycloalkyl group having 3-6 carbon atoms, such as cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl
- R 2 and R 3 can form together with the nitrogen to which they are bonded a 4-8 membered saturated heterocyclic ring, such as an azetidine, a pyrrolidine, a piperidine, or a 1 H-azepine ring.
- Such rings may contain 1 or more additional heteroatoms selected from O, S or NR 5 to form rings such as a morpholine, a thiomorpholine, a hexahydro-1 ,4-oxazepine, a piperazine, a homo- piperazine, an imidazolidine or a tetrahydrothiazole ring
- 4-8 membered saturated heterocyclic ring comprising 1 or 2 heteroatoms selected from O, S and NR 4 , as used I the definition of Y, is examplified by rings such as morpholin-4-yl, piperazin-4-yl, pyrrolidin-1-yl and piperidin-1 yl.
- 5- or 6-membered aromatic heterocyclic group containing 1-4 N atoms is examplified by rings such as pyridyl, pyrrolyl, imidazolyl, pyrazinyl and tetrazol-5-yl.
- Ri and Y can form together with the nitrogen to which they are bonded a 5-8 membered heterocyclic ring, optionally comprising a further heteroatom selected from O, S, NR 4 and NO.
- examples of such rings are piperidin-1 - yl, piperazin-1-yl, 4-oxo-piperazin-1-yl and diazepan-1-yl.
- halogen means F, Cl, Br, or I.
- F is preferred.
- a preferred halogen substituted alkyl group is trifluoromethyl.
- Preferred in the invention are those 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives according to formula I wherein R represents a trifluoromethyl substituent at the meta position of the 4-phenyl group.
- 4-phenyl-6-substituted pyrimidine-2-carbonitrile derivatives of the invention are: - 4-(piperazin-1-yl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile;
- compositions comprising a 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivative having general formula I, or a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable auxilliaries.
- the 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives of general Formula I can be prepared by the use of methods known in the art of organic chemistry in general.
- compounds of general formula I wherein X represents NR 1 , and R-i, R and Y have the meaning as previously defined may be prepared as depicted in Scheme 1.
- Reaction of 2-methylsulfanyl-4,6-dichloropyrimidine (II) with an amine of formula R 1 -NH-Y, wherein any further functional groups present in Y may carry an appropriate protecting group provides compounds with general formula (III).
- Oxidation of a sulfide of formula (III) with an oxidation reagent e.g.
- compound of formula (VIII) can be prepared from compounds of formula (VII) by reductive amination using an aldehyde and a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride or a resin bond reducing agent (Scheme 3).
- Scheme 3
- compounds of general formula (I) can be synthesised according to Scheme 6.
- Treatment of a compound of formula (XXI) with hydrochloric acid in methanol at refluxing temperature converts the nitrile moiety to a methyl ester with concomitant removal of benzyl group to give compounds of formula (XXII).
- Aminolysis and subsequent treatment with POCI3 produces the 6-chloride derivatives of formula (XXIV) as key intermediates, from which compounds of the invention of general formula I are obtained by reaction with nucleophiles of general formula H-X- Y, wherein X and Y have the meanings as previously defined.
- the compounds of the invention which can be in the form of a free base, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt.
- the pharmaceutically acceptable salts may also be obtained by treating the free base of formula I with an organic or inorganic acid such as, but not limited to, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.
- an organic or inorganic acid such as, but not limited to, hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid,
- Compounds of the invention may exist in solvated as well as in unsolvated forms, including hydrated forms.
- the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
- Compounds of the present invention may exist as amorphous forms, but also multiple crystalline forms may be possible. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of this invention.
- the 4-phenyl-6-substituted-py ⁇ midine-2-carbonitrile derivatives of the invention and their salts may contain a centre of chirality in one or more of the side chains R, Ri and Y and may therefore be obtained as a pure enantiomer, or as a mixture of enantiomers, or as a mixture containing diastereomers.
- Methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g. synthesis with chiral induction or starting from chiral intermediates, enantioselective enzymatic conversions, separation of stereoisomers or enantiomers using chromatography on chiral media. Such methods are for example described in Chirality in Industry (edited by A.N. Collins, G.N. Sheldrake and J. Crosby, 1992; John Wiley).
- the compounds of the invention were found to be inhibitors of human Cathepsins K and S and can therefore in a further aspect of the invention be used in therapy, and especially for the preparation of a medicament for the treatment of osteoporosis, atherosclerosis and related Cathepsin K and Cathepsin S dependent disorders, e.g. inflammation and immune disorders such as rheumatoid arthritis, chronic pain such as neuropathic pain, and further disorders related to abnormal bone resorption such as Paget's disease, osteoarthritis, osteolytic bone cancer and metastatic bone disease.
- inflammation and immune disorders such as rheumatoid arthritis
- chronic pain such as neuropathic pain
- further disorders related to abnormal bone resorption such as Paget's disease, osteoarthritis, osteolytic bone cancer and metastatic bone disease.
- the compounds of the invention may be administered enterally or parenterally, and for humans preferably in a daily dosage of 0.001-100 mg per kg body weight, preferably 0.01-10 mg per kg body weight.
- a daily dosage of 0.001-100 mg per kg body weight preferably 0.01-10 mg per kg body weight.
- the compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
- pharmaceutically suitable liquids the compounds can also be applied in the form of a solution, suspension, emulsion, e.g.
- Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
- Metachloroperoxybenzoic acid MCPBA
- dimethylformamide DMF
- NMP N- methylpyrolidinone
- DCM dimethylsulfoxide
- DMSO dimethylsulfoxide
- THF tetrahydrofuran
- DME 1 ,2-dimethoxyethane
- HPLC high pressure liquid chromatography
- DIPEA diisopropylethylamine
- TAA triethylamine
- TFA 1,2-dimethoxyethane
- HPLC high pressure liquid chromatography
- DIPEA diisopropylethylamine
- TAA triethylamine
- broad broad
- singlet s
- d doublet
- TMA trifluoroacetic acid
- TFA tert-butyloxycarbonyl
- Boc 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCI
- EDCI 1-hydroxy- benzotriazole
- 4,6-Dichloro-2-methylsulfanylpyrimidine (1Og) was dissolved in dichloro- methane (200 ml) and triethylamine (20.6 g) was added. The mixture was stirred at room temperature and piperazine-1-carboxylic acid terf-butyl ester (9.54 g) was added in portions. The mixture was stirred at room temperature overnight. Mixture was washed with water (200ml) then brine (100ml).
- Example 2a 4-[4-(2-Methoxy-ethyl)-piperazin-1 -yl1-6-(3-trifluoromethv-phenyl)- PVrimidine-2-carbonitrile
- Example 4 4-[4-(2-ferf-butyloxycarbonylethyl)-piperazin-1 -yl1-6-(3-trifluoromethyl- phenyl)pyrimidine-2-carbonitrile
- Example 5 4-[4-(2-carboxy-ethyl)-piperazin-1 -yl1-6-(3-trifluoromethyl-phenyl)- pyrimidine-2-carbonitrile trifluoroacetic acid salt
- Example 8 4-(4-Cvclopropyl-piperazin-1-yl)-6-(trifluoromethyl-phenyl)-pyrimidine-2- carbonitrile hydrochloric acid salt
- Reaction mixture was filtered through a celite pad, washed with ethyl acetate and concentrated in vacuo.
- the residual brown gum was columned on silica gel using heptane and ethyl acetate (1 :1 ) as eluant.
- Example 14 4-(4-Methyl-[1 ,41diazepan-1-yl)-6-(3-trifluoromethyl-phenyl)-pyrimidine- 2-carbonitrile
- 3-Bromo-6-methoxy-benzotrifluoride (5 g) was dissolved in dry THF (100 ml) and the mixture was cooled to -78 0 C under nitrogen. n-BuLi (12.25 ml of 1.6M solution in hexanes) was added drop wise over 10 minutes. Mixture was stirred at - 78 0 C for 10 minutes. Triisopropyl borate (3.87 g;) was added in one portion and the mixture was stirred at -78 0 C for 30 minutes before being allowed to warm to RT. Mixture was quenched by addition of water (50 ml) and acetic acid (1 ml).
- Example 18a 2- ⁇ 4-[2-Cvano-6-(4-methoxy-3-trifluoromethyl-phenyl)-pyrimidin-4-yl1-piperazin-1-yl)- acetamide trifluoroacetic acid salt
- Example 21 4-Hvdroxy-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile mCPBA (550 mg, 70% w/w) was added to a solution of 2-methylthio-6-(3- trifluoromethyl-phenyl)-pyrimidin-4-ol (200 mg, 0.75 mmol) in acetonitrile (7ml). After
- Example 22a 4-(2-Piperidin-1 -yl-ethoxy)-6-(3-trifluoromethyl-phenyl)-pyrimidine-2- carbonitrile
- the inhibitory activity of the compounds of the invention was demonstrated in vitro by measuring the inhibition of recombinant human Cathepsin K as follows: To a 384 well microtitre plate is added 5 ⁇ l of a 100 ⁇ M solution of test compound in assay buffer (10OmM sodium acetate pH5.5, 5mM EDTA, 5mM dithiothreitol) with 10% dimethylsulfoxide (DMSO), plus 10 ⁇ l of 100 ⁇ M solution of the substratre Z-Phe- Arg-AMC (Bachem; 7-amido-coumarine derivative of the dipeptide N- benzyloxycarbonyl-Phe-Arg-OH) in assay buffer and 25 ⁇ l of assay buffer.
- assay buffer 10OmM sodium acetate pH5.5, 5mM EDTA, 5mM dithiothreitol
- DMSO dimethylsulfoxide
- Compounds of the invention typically have a plC 5 o (negative logarithm of the IC 5 O concentration) for inhibition of human cathepsin K of more than 6, preferably more than 7 and most preferably a plC 5 o of more than 8, such as for the compounds of Examples 1. 2a, 2b, 3, 5, 6, 8, 12, 14, 13, 16k, 16n, 16o, 17, 22a, 22b, 22c
- the inhibitory activity of the compounds of the invention was demonstrated in vitro by measuring the inhibition of recombinant human Cathepsin S as follows: To a 384 well microtitre plate is added 10 ⁇ l of a 100 ⁇ M solution of test compound in assay buffer (10OmM sodium acetate pH5.5, 5mM EDTA, 5mM dithiothreitol) with 10% dimethylsulfoxide (DMSO), plus 20 ⁇ l of 250 ⁇ M solution of the substratre Z-VaI-VaI -Arg-AMC (Bachem; 7-amido-coumarine derivative of the tripeptide N- benzyloxycarbonyl-Val-Val-Arg-OH) in assay buffer and 45 ⁇ l of assay buffer.
- assay buffer 10OmM sodium acetate pH5.5, 5mM EDTA, 5mM dithiothreitol
- DMSO dimethylsulfoxide
- Enzyme activity is determined by measuring the fluorescence of the liberated aminomethylcoumarin at 44OnM using 39OnM excitation, at 20 minutes. Percentage enzyme activity is calculated by comparison of this activity to that of a solution containing no inhibitor.
- Compounds are subsequently subjected to a dose response curve analysis in order to determine IC 5 O values for active compounds (where IC 5 O is the concentration of test compound causing 50 % inhibition of the enzymatic activity).
- Compounds of the invention typically have a plC 5 o (negative logarithm of the IC 5 O concentration) for inhibition of human cathepsin S of more than 6. Most compounds of the invention have a plC 5 o of more than 7.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pain & Pain Management (AREA)
- Cardiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2006298775A AU2006298775A1 (en) | 2005-09-23 | 2006-09-21 | 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives |
NZ566475A NZ566475A (en) | 2005-09-23 | 2006-09-21 | 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives |
CN2006800348456A CN101268058B (en) | 2005-09-23 | 2006-09-21 | 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives |
BRPI0616186-3A BRPI0616186A2 (en) | 2005-09-23 | 2006-09-21 | 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivative or a pharmaceutically acceptable salt thereof, pharmaceutical composition, and use of a 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivative |
EP06806788A EP1928842B1 (en) | 2005-09-23 | 2006-09-21 | 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives |
CA2621040A CA2621040C (en) | 2005-09-23 | 2006-09-21 | 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives |
AT06806788T ATE449080T1 (en) | 2005-09-23 | 2006-09-21 | 4-PHENYL-6-SUBSTITUTED PYRIMIDINE-2 CARBONITRILE DERIVATIVES |
DE602006010581T DE602006010581D1 (en) | 2005-09-23 | 2006-09-21 | 4-PHENYL-6-SUBSTITUTED PYRIMIDIN-2-CARBONITRILE DERIVATIVES |
JP2008531697A JP5060484B2 (en) | 2005-09-23 | 2006-09-21 | 4-Phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives |
IL189893A IL189893A0 (en) | 2005-09-23 | 2008-03-03 | 4-phenyl-6-substituted-pyrimidine-2- |
NO20081128A NO20081128L (en) | 2005-09-23 | 2008-03-04 | 4-phenyl-6-substituted-pyrimidine-2-carbonitrile |
HK09101523.5A HK1124319A1 (en) | 2005-09-23 | 2009-02-18 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05108810.2 | 2005-09-23 | ||
EP05108810 | 2005-09-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007039470A1 true WO2007039470A1 (en) | 2007-04-12 |
Family
ID=35466129
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2006/066562 WO2007039470A1 (en) | 2005-09-23 | 2006-09-21 | 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives |
Country Status (19)
Country | Link |
---|---|
EP (1) | EP1928842B1 (en) |
JP (1) | JP5060484B2 (en) |
KR (1) | KR20080046716A (en) |
CN (1) | CN101268058B (en) |
AR (1) | AR056086A1 (en) |
AT (1) | ATE449080T1 (en) |
AU (1) | AU2006298775A1 (en) |
BR (1) | BRPI0616186A2 (en) |
CA (1) | CA2621040C (en) |
DE (1) | DE602006010581D1 (en) |
ES (1) | ES2334714T3 (en) |
HK (1) | HK1124319A1 (en) |
IL (1) | IL189893A0 (en) |
NO (1) | NO20081128L (en) |
NZ (1) | NZ566475A (en) |
PE (1) | PE20070438A1 (en) |
TW (1) | TW200745055A (en) |
WO (1) | WO2007039470A1 (en) |
ZA (1) | ZA200802088B (en) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007148064A1 (en) * | 2006-06-23 | 2007-12-27 | Astrazeneca Ab | Pteridine derivatives and their use as cathespin inhibitors |
US8362248B2 (en) | 2005-01-10 | 2013-01-29 | Arena Pharmaceuticals, Inc. | Substituted pyridinyl and pyrimidinyl derivatives as modulators of metabolism and the treatment of disorders related thereto |
US8410119B2 (en) | 2003-07-14 | 2013-04-02 | Arena Pharmaceuticals, Inc. | Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto |
US8546429B2 (en) | 2003-07-11 | 2013-10-01 | Arena Pharmaceuticals, Inc. | 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto |
JP2013541574A (en) * | 2010-11-05 | 2013-11-14 | エフ.ホフマン−ラ ロシュ アーゲー | Pyrrolidine derivatives used as cathepsin inhibitors |
US8933083B2 (en) | 2003-01-14 | 2015-01-13 | Arena Pharmaceuticals, Inc. | 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia |
US9328118B2 (en) | 2012-04-17 | 2016-05-03 | Astellas Pharma Inc. | Nitrogen-containing bicyclic aromatic heterocyclic compound |
US9981918B2 (en) | 2011-08-30 | 2018-05-29 | Chdi Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
US10258621B2 (en) | 2014-07-17 | 2019-04-16 | Chdi Foundation, Inc. | Methods and compositions for treating HIV-related disorders |
US10894787B2 (en) | 2010-09-22 | 2021-01-19 | Arena Pharmaceuticals, Inc. | Modulators of the GPR119 receptor and the treatment of disorders related thereto |
US11007175B2 (en) | 2015-01-06 | 2021-05-18 | Arena Pharmaceuticals, Inc. | Methods of treating conditions related to the S1P1 receptor |
US11299478B2 (en) | 2018-03-28 | 2022-04-12 | Hanlim Pharmaceutical Co., Ltd. | 2-cyanopyrimidin-4-yl carbamate or urea derivative or salt thereof, and pharmaceutical composition including same |
US11534424B2 (en) | 2017-02-16 | 2022-12-27 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of primary biliary cholangitis |
US11884626B2 (en) | 2015-06-22 | 2024-01-30 | Arena Pharmaceuticals, Inc. | Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2732806A1 (en) | 2008-08-04 | 2010-02-11 | John Wityak | Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
KR20120131161A (en) * | 2010-01-25 | 2012-12-04 | 씨에이치디아이 파운데이션, 인코포레이티드 | Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
WO2013033068A1 (en) | 2011-08-30 | 2013-03-07 | Stephen Martin Courtney | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003020278A1 (en) * | 2001-08-30 | 2003-03-13 | Novartis Ag | Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin k inhibitory activity for the treatment of inflammations and other diseases |
WO2003020721A1 (en) * | 2001-08-30 | 2003-03-13 | Novartis Ag | Pyrrolo pyrimidines as agents for the inhibition of cystein proteases |
WO2004000819A1 (en) * | 2002-06-24 | 2003-12-31 | Astrazeneca Ab | New use of pyrimidine - or triazine- 2-carbonitiles for treating diseases associated with cysteine protease activity and novel pyrimidine-2-carbonitile derivatives |
WO2004000843A1 (en) * | 2002-06-24 | 2003-12-31 | Astrazeneca Ab | NOVEL PURINE- OR PYRROLOL[2,3-d]PYRIMIDINE-2-CARBONITILES FOR TREATING DISEASES ASSOCIATED WITH CYSTEINE PROTEASE ACTIVITY |
WO2004020441A1 (en) * | 2002-08-30 | 2004-03-11 | Novartis Ag | Hetereoaryl nitrile derivatives |
-
2006
- 2006-09-14 TW TW095134051A patent/TW200745055A/en unknown
- 2006-09-21 CN CN2006800348456A patent/CN101268058B/en not_active Expired - Fee Related
- 2006-09-21 NZ NZ566475A patent/NZ566475A/en unknown
- 2006-09-21 BR BRPI0616186-3A patent/BRPI0616186A2/en not_active IP Right Cessation
- 2006-09-21 EP EP06806788A patent/EP1928842B1/en not_active Not-in-force
- 2006-09-21 ES ES06806788T patent/ES2334714T3/en active Active
- 2006-09-21 DE DE602006010581T patent/DE602006010581D1/en active Active
- 2006-09-21 JP JP2008531697A patent/JP5060484B2/en not_active Expired - Fee Related
- 2006-09-21 CA CA2621040A patent/CA2621040C/en not_active Expired - Fee Related
- 2006-09-21 WO PCT/EP2006/066562 patent/WO2007039470A1/en active Application Filing
- 2006-09-21 AU AU2006298775A patent/AU2006298775A1/en not_active Abandoned
- 2006-09-21 KR KR1020087008796A patent/KR20080046716A/en not_active Application Discontinuation
- 2006-09-21 AT AT06806788T patent/ATE449080T1/en not_active IP Right Cessation
- 2006-09-22 PE PE2006001151A patent/PE20070438A1/en not_active Application Discontinuation
- 2006-09-25 AR ARP060104157A patent/AR056086A1/en unknown
-
2008
- 2008-03-03 IL IL189893A patent/IL189893A0/en unknown
- 2008-03-04 NO NO20081128A patent/NO20081128L/en not_active Application Discontinuation
- 2008-03-05 ZA ZA200802088A patent/ZA200802088B/en unknown
-
2009
- 2009-02-18 HK HK09101523.5A patent/HK1124319A1/xx not_active IP Right Cessation
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003020278A1 (en) * | 2001-08-30 | 2003-03-13 | Novartis Ag | Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin k inhibitory activity for the treatment of inflammations and other diseases |
WO2003020721A1 (en) * | 2001-08-30 | 2003-03-13 | Novartis Ag | Pyrrolo pyrimidines as agents for the inhibition of cystein proteases |
WO2004000819A1 (en) * | 2002-06-24 | 2003-12-31 | Astrazeneca Ab | New use of pyrimidine - or triazine- 2-carbonitiles for treating diseases associated with cysteine protease activity and novel pyrimidine-2-carbonitile derivatives |
WO2004000843A1 (en) * | 2002-06-24 | 2003-12-31 | Astrazeneca Ab | NOVEL PURINE- OR PYRROLOL[2,3-d]PYRIMIDINE-2-CARBONITILES FOR TREATING DISEASES ASSOCIATED WITH CYSTEINE PROTEASE ACTIVITY |
WO2004020441A1 (en) * | 2002-08-30 | 2004-03-11 | Novartis Ag | Hetereoaryl nitrile derivatives |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8933083B2 (en) | 2003-01-14 | 2015-01-13 | Arena Pharmaceuticals, Inc. | 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia |
US8546429B2 (en) | 2003-07-11 | 2013-10-01 | Arena Pharmaceuticals, Inc. | 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto |
US8410119B2 (en) | 2003-07-14 | 2013-04-02 | Arena Pharmaceuticals, Inc. | Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto |
US8362248B2 (en) | 2005-01-10 | 2013-01-29 | Arena Pharmaceuticals, Inc. | Substituted pyridinyl and pyrimidinyl derivatives as modulators of metabolism and the treatment of disorders related thereto |
WO2007148064A1 (en) * | 2006-06-23 | 2007-12-27 | Astrazeneca Ab | Pteridine derivatives and their use as cathespin inhibitors |
US10894787B2 (en) | 2010-09-22 | 2021-01-19 | Arena Pharmaceuticals, Inc. | Modulators of the GPR119 receptor and the treatment of disorders related thereto |
JP2013541574A (en) * | 2010-11-05 | 2013-11-14 | エフ.ホフマン−ラ ロシュ アーゲー | Pyrrolidine derivatives used as cathepsin inhibitors |
US9981918B2 (en) | 2011-08-30 | 2018-05-29 | Chdi Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
US9328118B2 (en) | 2012-04-17 | 2016-05-03 | Astellas Pharma Inc. | Nitrogen-containing bicyclic aromatic heterocyclic compound |
US9585889B2 (en) | 2012-04-17 | 2017-03-07 | Astellas Pharma Inc. | Nitrogen-containing bicyclic aromatic heterocyclic compound |
US10258621B2 (en) | 2014-07-17 | 2019-04-16 | Chdi Foundation, Inc. | Methods and compositions for treating HIV-related disorders |
US11007175B2 (en) | 2015-01-06 | 2021-05-18 | Arena Pharmaceuticals, Inc. | Methods of treating conditions related to the S1P1 receptor |
US11884626B2 (en) | 2015-06-22 | 2024-01-30 | Arena Pharmaceuticals, Inc. | Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders |
US11534424B2 (en) | 2017-02-16 | 2022-12-27 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of primary biliary cholangitis |
US11299478B2 (en) | 2018-03-28 | 2022-04-12 | Hanlim Pharmaceutical Co., Ltd. | 2-cyanopyrimidin-4-yl carbamate or urea derivative or salt thereof, and pharmaceutical composition including same |
Also Published As
Publication number | Publication date |
---|---|
EP1928842A1 (en) | 2008-06-11 |
ZA200802088B (en) | 2008-11-26 |
AU2006298775A1 (en) | 2007-04-12 |
NO20081128L (en) | 2008-06-18 |
ES2334714T3 (en) | 2010-03-15 |
CN101268058A (en) | 2008-09-17 |
TW200745055A (en) | 2007-12-16 |
HK1124319A1 (en) | 2009-07-10 |
IL189893A0 (en) | 2008-08-07 |
CA2621040C (en) | 2014-01-28 |
NZ566475A (en) | 2010-03-26 |
CN101268058B (en) | 2013-02-27 |
BRPI0616186A2 (en) | 2011-06-07 |
JP2009508912A (en) | 2009-03-05 |
EP1928842B1 (en) | 2009-11-18 |
KR20080046716A (en) | 2008-05-27 |
ATE449080T1 (en) | 2009-12-15 |
PE20070438A1 (en) | 2007-06-13 |
AR056086A1 (en) | 2007-09-19 |
DE602006010581D1 (en) | 2009-12-31 |
JP5060484B2 (en) | 2012-10-31 |
CA2621040A1 (en) | 2007-04-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1928842B1 (en) | 4-phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives | |
US7326715B2 (en) | 4-Phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives | |
US7589095B2 (en) | 4-phenyl-pyrimidine-2-carbonitrile derivatives | |
CA2604967C (en) | Pyrimidine derivatives and their use as p2y12 receptor antagonist | |
HU211968A9 (en) | Heterocyclic amines useful in the therapy of asthma and inflammation of the respiratory tract | |
IL176478A (en) | Derivatives of 1-piperazine- and 1-homopiperazine-carboxylates, preparation method thereof and use of same as inhibitors of the faah enzyme | |
EP2410855A1 (en) | Process for the preparation of alogliptin | |
ITOH et al. | Non-glutamate type pyrrolo [2, 3-d] pyrimidine antifolates. I: Synthesis and biological properties of pyrrolo [2, 3-d] pyrimidine antifolates containing tetrazole congener of glutamic acid | |
RU2328495C2 (en) | Benzofuran derivatives | |
CA2373944C (en) | Cathecol hydrazone derivatives, process for preparing the same and pharmaceutical composition containing the same | |
KR20220024051A (en) | Novel arginase inhibitors | |
US4729995A (en) | Pyrimidine 2,4-dioxamate compounds and pharmaceutical compositions | |
ZA200609723B (en) | 4-Phenyl-pyrimidine-2-carbonitrile derivatives | |
WO2006040300A1 (en) | 4-cycloalkyl-pyrimidine-2-carbonitrile derivatives | |
Terentjeva et al. | 06-JCR1503632 FIRST PROOF | |
JPH06107658A (en) | New pyrazine derivative | |
JPH0632782A (en) | Pyrazole derivative and method for producing the same and medicine containing the same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2006806788 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2621040 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12008500520 Country of ref document: PH Ref document number: 189893 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 566475 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006298775 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/a/2008/003818 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2008531697 Country of ref document: JP Ref document number: 200680034845.6 Country of ref document: CN |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2006298775 Country of ref document: AU Date of ref document: 20060921 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 2006298775 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020087008796 Country of ref document: KR |
|
WWP | Wipo information: published in national office |
Ref document number: 2006806788 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: PI0616186 Country of ref document: BR Kind code of ref document: A2 Effective date: 20080320 |