WO2013171318A1 - Benzo[1,3]dioxine derivatives and their use as lpar5 antagonists - Google Patents
Benzo[1,3]dioxine derivatives and their use as lpar5 antagonists Download PDFInfo
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- WO2013171318A1 WO2013171318A1 PCT/EP2013/060172 EP2013060172W WO2013171318A1 WO 2013171318 A1 WO2013171318 A1 WO 2013171318A1 EP 2013060172 W EP2013060172 W EP 2013060172W WO 2013171318 A1 WO2013171318 A1 WO 2013171318A1
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- alkyl
- dioxine
- benzo
- carboxylic acid
- dicyclohexyl
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- TWSIYGATPWEKBK-UHFFFAOYSA-N C1OCOc2ccccc12 Chemical compound C1OCOc2ccccc12 TWSIYGATPWEKBK-UHFFFAOYSA-N 0.000 description 1
- BRJZQGQFLRQVTP-UHFFFAOYSA-N CC(C)(C)c1ccc2OC(C(O)=O)OC(C3CCCCC3)(C3CCCCC3)c2c1 Chemical compound CC(C)(C)c1ccc2OC(C(O)=O)OC(C3CCCCC3)(C3CCCCC3)c2c1 BRJZQGQFLRQVTP-UHFFFAOYSA-N 0.000 description 1
- XKEPFFWGTPYHNI-UHFFFAOYSA-N Cc1cc(Cl)cc2c1OC(C(O)=O)OC2(C1CCCCC1)C1CCCCC1 Chemical compound Cc1cc(Cl)cc2c1OC(C(O)=O)OC2(C1CCCCC1)C1CCCCC1 XKEPFFWGTPYHNI-UHFFFAOYSA-N 0.000 description 1
- CBGGTXULLJKPGU-UHFFFAOYSA-N Cc1cc(OC)cc2c1C(C1CCCCC1)(C1CCCCC1)OC(C(O)=O)O2 Chemical compound Cc1cc(OC)cc2c1C(C1CCCCC1)(C1CCCCC1)OC(C(O)=O)O2 CBGGTXULLJKPGU-UHFFFAOYSA-N 0.000 description 1
- NSJWCGRUQOIQQH-UHFFFAOYSA-N NC(N1)=NOC1=O Chemical compound NC(N1)=NOC1=O NSJWCGRUQOIQQH-UHFFFAOYSA-N 0.000 description 1
- PHPGVCMRZJTTQC-UHFFFAOYSA-N NC(O1)=NNC1=O Chemical compound NC(O1)=NNC1=O PHPGVCMRZJTTQC-UHFFFAOYSA-N 0.000 description 1
- ULRPISSMEBPJLN-UHFFFAOYSA-N Nc1nnn[nH]1 Chemical compound Nc1nnn[nH]1 ULRPISSMEBPJLN-UHFFFAOYSA-N 0.000 description 1
- NQYVUFAEKZROKZ-UHFFFAOYSA-N OC(C(OC(C1CCCCC1)(C1CCCCC1)c1c2)Oc1cc(F)c2Cl)=O Chemical compound OC(C(OC(C1CCCCC1)(C1CCCCC1)c1c2)Oc1cc(F)c2Cl)=O NQYVUFAEKZROKZ-UHFFFAOYSA-N 0.000 description 1
- UNPSUVUWCYRLAV-UHFFFAOYSA-N OC(C(OC(C1CCCCC1)(C1CCCCC1)c1c2)Oc1ccc2I)=O Chemical compound OC(C(OC(C1CCCCC1)(C1CCCCC1)c1c2)Oc1ccc2I)=O UNPSUVUWCYRLAV-UHFFFAOYSA-N 0.000 description 1
- OJZKUQVZXKOGDE-UHFFFAOYSA-N OC(C(OC(C1CCCCC1)(C1CCCCC1)c1c2)Oc1ccc2OC(F)(F)F)=O Chemical compound OC(C(OC(C1CCCCC1)(C1CCCCC1)c1c2)Oc1ccc2OC(F)(F)F)=O OJZKUQVZXKOGDE-UHFFFAOYSA-N 0.000 description 1
- YUCIBCCPUGNTDT-UHFFFAOYSA-N OC(C1Oc2c(Cc3ccccc3)c3ccccc3cc2C(C2CCCCC2)(C2CCCCC2)O1)=O Chemical compound OC(C1Oc2c(Cc3ccccc3)c3ccccc3cc2C(C2CCCCC2)(C2CCCCC2)O1)=O YUCIBCCPUGNTDT-UHFFFAOYSA-N 0.000 description 1
- VLPQUKUASDWSKS-UHFFFAOYSA-N OC(C1Oc2cc(N3CCOCC3)ccc2C(C2CCCCC2)(C2CCCCC2)O1)=O Chemical compound OC(C1Oc2cc(N3CCOCC3)ccc2C(C2CCCCC2)(C2CCCCC2)O1)=O VLPQUKUASDWSKS-UHFFFAOYSA-N 0.000 description 1
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- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
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- 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
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- 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
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- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
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- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- Benzo[1 ,3]dioxine derivatives and their use as LPAR5 antagonists The present invention relates to compounds of the formula I,
- the compounds of the formula I are valuable pharmacologically active compounds for use in the treatment of diverse disorders.
- Compounds of the formula I exhibit a strong anti-aggregating effect on platelets and thus an anti-thrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardiovascular disorders like thromboembolic diseases or restenoses.
- compounds of the formula I inhibit LPA-mediated activation of mast cells and microglia cells.
- the compounds of the invention are antagonists of the platelet LPA receptor LPAR5 (GPR92) and can in general be applied in conditions in which an undesired activation of the platelet LPA receptor LPAR5, the mast cell LPA receptor LPAR5 or the microglia cell LPA receptor LPAR5 is present, or for the cure or prevention of which an inhibition of the platelet, mast cell or microglia cell LPA receptor LPAR5 is intended.
- the invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in medicaments, and pharmaceutical compositions comprising them.
- thrombotic complications are one of the major causes of death.
- pathological thrombus formation examples include deep vein thrombosis, venous and arterial thromboembolism,
- thrombophlebitis coronary and cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, disseminated intravascular coagulation, transient ischemic attacks, strokes, acute myocardial infarction, peripheral vascular disease, preeclampsia/eclampsia, and thrombotic cytopenic purpura.
- invasive procedures including insertion of endovascular devices and protheses, carotid endarterectomy, angioplasty, CABG (coronary artery bypass graft) surgery, vascular graft surgery, and stent placements, thrombotic and restenotic
- Platelet aggregation plays a critical role in these intravascular thrombotic events.
- Platelets can be activated by mediators released from circulating cells and damaged endothelial cells lining the vessel or by exposed subendothelial matrix molecules such as collagen, lysophosphatidic acid or by thrombin, which is formed in the coagulation cascade.
- mediators released from circulating cells and damaged endothelial cells lining the vessel or by exposed subendothelial matrix molecules such as collagen, lysophosphatidic acid or by thrombin, which is formed in the coagulation cascade.
- platelets which normally circulate freely in the vasculature, and other cells, accumulate at the site of a vessel injury to form a thrombus and recruit more platelets to the developing thrombus.
- thrombi can grow to a sufficient size to partly or completely block arterial blood vessels. In veins thrombi can also form in areas of stasis or slow blood flow.
- venous thrombi can create emboli that travel through the circulatory system, as they easily detach portions of themselves. These traveling emboli can block other vessels, such as pulmonary or coronary arteries, which can result in the above-mentioned pathological outcomes such as pulmonary or coronary embolism.
- pulmonary or coronary arteries can block other vessels, such as pulmonary or coronary arteries, which can result in the above-mentioned pathological outcomes such as pulmonary or coronary embolism.
- morbidity and mortality arise primarily after embolization or distant blockade of vessels, whereas arterial thrombi cause serious pathological conditions by local blockade.
- Lysophosphatidic acid is an important bioactive phospholipid with a wide range of cellular functions. Levels of LPA are tightly regulated via its synthesis, controlled by two different pathways. The first consisting of phospholipase D (PLD) and phospholipase A2 (PLA 2 ) activity, the second consisting of PLA 2 and
- lysophospholipase D lysoPLD activity.
- LPA lysophospholipase D
- the most commonly used LPA in laboratory praxis is 18:1 LPA (1 -acyl-2-hydroxy-sn-glycero-3-phosphate).
- LPA long-chain fatty acid chain
- a key enzyme for LPA synthesis is autotaxin (ATX), Enpp2 in mice.
- LPA receptors belong to the class A (Rhodopsin-like class) of G protein-coupled receptors (GPCRs).
- GPCRs G protein-coupled receptors
- LPAR5 has been identified in mouse and human dorsal root ganglia and reduced perception of pain was seen in LPAR5 " ' " mice (Oh et al., J Biol Chem (2008), 283, 21054-21064; Kinloch et al., Expert Opin Ther Targets (2005), 9, 685-698).
- alkyl-LPA receptor is neither an EDG-type LPA receptor nor GPR23 (Tokumura et al., Biochem J (2002), 365, 617-628; Noguchi et al., J Biol Chem (2003), 278, 25600- 25606; Khandoga et al., J Thromb Haemost (2007), 5 Supplement 2: P-M-246 (ISTH 2007)).
- LPAR5 can be activated more strongly with alkyl-LPA than acyl-LPA (Williams et al., J Biol Chem (2009), 284, 14558-14571 ).
- LPA-receptors LPAR4 and LPAR5 are highly expressed by human platelets (Amisten et al., Thromb Res (2008), 122, 47-57). In contrast to LPAR5, which is coupled to G q , LPAR4 couples to G s and can therefore be excluded to participate in LPA-mediated activation of human platelets.
- LPAR5 was discussed to be the central LPA-receptor responsible for LPA-mediated activation in human platelets (Khandoga et al., Platelets (2008), 19, 415-427). High expression of LPAR5 in human mast cell lines has been demonstrated, for example by Lundequist (Lundequist, J Allergy Clin Immunol (2008), 121 , Suppl 1 , Abstr 518), and further analyses.
- Mast cells are part of the immune system and generated as precursor cells in the bone marrow, differentiating to mature mast cells in the homing tissue. Mast cells participate in a variety of pathophysiological processes that range from antimicrobial defense to anaphylaxis and inflammatory arthritis and have thus been discussed to be related to allergic responses. When activated, mast cells degranulate and release a plethora of mediators (cytokines such as TNFa, MCP-1 , Rantes) into the interstitium. This indicates a direct contribution of mast cells to neuropathic pain by releasing algogenic mediators after degranulation.
- mediators cytokines such as TNFa, MCP-1 , Rantes
- mast cells are involved in a variety of pathologies apart from allergic responses related to pathologies with an inflammatory component.
- diseases comprise hyperalgesia, asthma, multiple sclerosis and angiogenesis to name only a few (Zuo et al., Pain (2003), 105, 467-479; Toews et al., Biochim Biophys Acta (2002), 1582, 240-250; Norby, APMIS (2002), 1 10, 355-371 ).
- LPAR5 is highly expressed not only in mast cells but as well in microglia cells underlines the central role of LPAR5 in the development and progression of inflammatory disorders, such as hyperalgesia, asthma, multiple sclerosis, angiogenesis and others. Further experiments confirmed that in human platelets and in human mast cells and microglia cells LPAR5 is the key LPA-receptor responsible for LPA-mediated activation. In view of the relevance of LPAR5 for various disease states there is a need for compounds which efficiently inhibit LPAR5 and, for example, consequently inhibit mast cell activation or platelet activation in pathological settings, and allow novel therapeutic options for treating disorders.
- LPAR5 antagonists which antagonize the effect of endogenous LPA on its LPAR5 receptor and which have further advantageous properties, for instance stability in plasma and liver and selectivity versus other receptors whose agonism or antagonism is not intended.
- This object is achieved in accordance with the invention by providing the benzo[1 ,3]dioxine derivatives of the formula I, which exhibit excellent LPAR5 antagonistic activity and are favorable agents with high bioavailability, and can be used for inhibiting platelet aggregation and treating thromboembolic diseases, for example.
- Specifically disclosed compounds in which one of the groups corresponding to Z 1 and Z 2 is cyclohexyl are 6-chloro-4-cyclohexyl-4- phenyl-4H-benzo[1 ,3]dioxine-2-carboxylic acid and its methyl ester and 6-chloro-4,4- dicyclohexyl-4H-benzo[1 ,3]dioxine-2-carboxylic acid.
- 6-chloro-4-cyclohexyl-4- phenyl-4H-benzo[1 ,3]dioxine-2-carboxylic acid and its methyl ester 6-chloro-4,4- dicyclohexyl-4H-benzo[1 ,3]dioxine-2-carboxylic acid.
- Humbert et al. in which the groups corresponding to Z 1 and Z 2 are not cyclohexyl, data are given which show their hypotriglyceridaemic and hypocholesterolaemic activity and in view of which the compounds are regarded as useful for treatment of hyperlipaemia.
- An activity of the compounds on platelet aggregation is neither disclosed nor suggested in GB 2022579 and in D. Humbert et al.
- Other 4H-benzo[1 ,3]dioxine-2-carboxylic acids and derivatives thereof are described, for example, in J. A. Turner et al., J. Agric. Food Chem. (2002), 50, 4554- 4566, which relates to herbicidal acetyl coenzyme A carboxylase inhibitors, or in US 4056540, which relates to compounds having anticonvulsant and antiarrhythmic activity.
- a subject of the present invention are the compounds of the formula I, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and the pharmaceutically acceptable salts thereof,
- A is selected from the series consisting of R 11 -O-C(O)-, R 12 -N(R 13 )-C(O)- and Het 1 ;
- R 1 , R 2 , R 3 and R 4 are independently of each other selected from the series consisting of hydrogen, halogen, (Ci-C 4 )-alkyl, Ar-(Ci-C 4 )-alkyl-, Ar, Het 2 , (Ci-C 4 )-alkyl-C(O)-, Ar-C(O)-, cyano, R 14 -N(R 15 )-C(O)-, Het 3 -C(O)-, hydroxy, (Ci-C 4 )-alkyl-O-, Ar-O-, Ar- (Ci-C 4 )-alkyl-O-, (Ci-C 4 )-alkyl-S(O) n -, Ar-S(O) n -, R 11 -N(R 12 )-S(O) 2 -, Het 3 -S(O) 2 -, (C C 4 )-alkyl-NH-, di((Ci-C
- R 11 , R 12 , R 13 , R 14 and R 15 are independently of each other selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl; one of the groups Z 1 and Z 2 is (C3-C8)-cycloalkyl and the other is selected from the series consisting of hydrogen, (Ci-CsJ-alkyl, (C3-C8)-cycloalkyl and phenyl, wherein all cycloalkyl groups are independently of each other unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine, (Ci-C 4 )-alkyl and (Ci-C 4 )-alkyl-O-, and the phenyl group is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (Ci-C 4 )-alkyl, cyano, (Ci-C 4 )-alkyl-O- and
- Ar is phenyl or an aromatic, 5-membered or 6-membered, monocyclic heterocycle which comprises one or two identical or different ring heteroatoms selected from the series consisting of N, O and S, which are all unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (Ci-C 4 )-alkyl, cyano, (d-C 4 )-alkyl-O- and (Ci-C 4 )-alkyl-S(O) n -;
- Het 1 is a partially unsaturated or aromatic, 5-membered or 6-membered, monocyclic heterocycle which comprises one to four identical or different ring heteroatoms selected from the series consisting of N, O and S, which is bonded via a ring carbon atom, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of (Ci-C 4 )-alkyl, hydroxy and oxo;
- Het 2 is a saturated, 4-membered to 7-membered, monocyclic heterocycle which comprises one or two identical or different ring heteroatoms selected from the series consisting of N, O and S, which is bonded via a ring carbon atom or a ring nitrogen atom, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl;
- Het 3 is a saturated 4-membered to 7-membered, monocyclic heterocycle which comprises a ring nitrogen atom via which Het 3 is bonded, and zero or one further ring heteroatom selected from the series consisting of N, O and S, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl; n is selected from the numbers 0, 1 and 2; wherein all alkyl groups are unsubstituted or substituted by one or more fluorine substituents; provided that the compound of the formula I is not 6-chloro-4-cyclohexyl-4-phenyl- 4H-benzo[1 ,3]dioxine-2-carboxylic acid, 6-chloro-4-cyclohexyl-4-phenyl-4H- benzo[1 ,3]dioxine-2-carboxylic acid methyl ester or 6-chloro-4,4-
- A is selected from the series consisting of R 11 -O-C(O)-, R 12 -N(R 13 )-C(O)- and Het 1 ;
- R 1 , R 2 , R 3 and R 4 are independently of each other selected from the series consisting of hydrogen, halogen, (Ci-C 4 )-alkyl, Ar-(Ci-C 4 )-alkyl-, Ar, Het 2 , (Ci-C 4 )-alkyl-C(O)-, Ar-C(O)-, R 14 -N(R 15 )-C(O)-, Het 3 -C(O)-, (Ci-C 4 )-alkyl-O-, Ar-O-, Ar-(Ci-C 4 )-alkyl-O-, (Ci-C 4 )-alkyl-S(O) n -, Ar-S(O) n -, R 11 -N(R 12 )-S(O)
- R 5 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl
- R 11 , R 12 , R 13 , R 14 and R 15 are independently of each other selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl; one of the groups Z 1 and Z 2 is (C3-C8)-cycloalkyl and the other is selected from the series consisting of hydrogen, (Ci-CsJ-alkyl, (C3-C8)-cycloalkyl and phenyl, wherein all cycloalkyl groups are independently of each other unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine, (Ci-C 4 )-alkyl and (Ci-C 4 )-alkyl-O-, and the phenyl group is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (Ci-C 4 )-alkyl, cyano, (Ci-C 4 )-alkyl-O- and
- Het 1 is a partially unsaturated or aromatic, 5-membered monocyclic heterocycle which comprises one to four identical or different ring heteroatoms selected from the series consisting of N, O and S, which is bonded via a ring carbon atom, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of (Ci-C 4 )-alkyl, hydroxy and oxo;
- Het 2 is a saturated, 4-mennbered to 7-mennbered, monocyclic heterocycle which comprises one or two identical or different ring heteroatoms selected from the series consisting of N, O and S, which is bonded via a ring carbon atom or a ring nitrogen atom, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl;
- Het 3 is a saturated 4-mennbered to 7-mennbered, monocyclic heterocycle which comprises a ring nitrogen atom via which Het 3 is bonded, and zero or one further ring heteroatom selected from the series consisting of N, O and S, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl; n is selected from the numbers 0, 1 and 2; wherein all alkyl groups are unsubstituted or substituted by one or more fluorine substituents; and all stereoisomeric forms thereof and mixtures of stereoisomeric forms in any ratio, and the pharmaceutically acceptable salts thereof.
- the present invention relates to compounds of the formula I, wherein
- A is selected from R 11 -O-C(O)- or Het 1 ;
- R 1 , R 2 , R 3 and R 4 are independently of each other selected from the series consisting of hydrogen, halogen, (Ci-C 4 )-alkyl, Ar-(Ci-C 4 )-alkyl-, Ar, Het 2 , (Ci-C 4 )-alkyl-C(O)-, Ar-C(O)-, R 14 -N(R 15 )-C(O)-, Het 3 -C(O)-, (Ci-C 4 )-alkyl-O-, Ar-O-, Ar-(Ci-C 4 )-alkyl-O-, R 11 -N(R 12 )-S(O) 2 -, Het 3 -S(O) 2 -, (Ci-C 4 )-alkyl-NH- and di((Ci-C 4 )-alkyl)N-, and either the groups R 1 and R 2 , or R 2 and R 3 , or R 3 and R 4 ,
- R 5 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl
- R 11 , R 12 , R 14 and R 15 are independently of each other selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl; one of the groups Z 1 and Z 2 is (C3-C8)-cycloalkyl and the other is selected from the series consisting of hydrogen, (Ci-C 4 )-alkyl, (C3-C8)-cycloalkyl and phenyl, wherein all cycloalkyl groups are independently of each other unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl, and the phenyl group is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen and (Ci-C 4 )-alkyl; Ar is phenyl or an aromatic, 5-membered or 6-mennbered, monocyclic heterocycle which comprises one or two identical or different ring heteroatoms
- Het 1 is selected from the series consisting of
- R 10 is selected from the series consisting of hydrogen and (Ci-C 4 )-alkyl
- Het 2 is a saturated, 5-membered or 6-membered, monocyclic heterocycle which comprises one or two identical or different ring heteroatoms selected from the series consisting of N, O and S, which is bonded via a ring carbon atom or a ring nitrogen atom, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl;
- Het 3 is a saturated 5-membered or 6-membered, monocyclic heterocycle which comprises a ring nitrogen atom via which Het 3 is bonded, and zero or one further ring heteroatom selected from the series consisting of N, O and S, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl; wherein all alkyl groups are unsubstituted or substituted by one or more fluorine substituents; and all stereoisomeric forms thereof and mixtures of stereoisomeric forms in any ratio, and the pharmaceutically acceptable salts thereof.
- the present invention relates to compounds of the formula I, wherein
- A is selected from the series consisting of R 11 -O-C(O)-,
- R 1 , R 2 , R 3 and R 4 are independently of each other selected from the series consisting of hydrogen, halogen, (CrC 4 )-alkyl, (Ci-C 4 )-perfluoroalkyl, (Ci-C 4 )-alkyl-O-, (Ci-C 4 )- perfluoroalkyl-O-, phenyl, pyrrolyl, pyridinyl, pyridinyl-O-, pyrrolidinyl-S(O)2-, morpholinyl, Ar-C(O)-, Ar-O-, di((Ci-C 4 )-alkyl)N-, Ar-(d-C 4 )-alkyl- and Ar-(d-C 4 )- alkyl-O-, and either the groups R 1 and R 2 , or R 2 and R 3 , or R 3 and R 4 , together with the carbon atoms carrying them, can form a benzene ring
- R 5 is hydrogen or methyl
- Z 1 and Z 2 are identical and are (C3-C8)-cycloalkyl, or one of the residues Z 1 and Z 2 is (C3-C8)-cycloalkyl and the other is hydrogen or phenyl;
- Ar is phenyl which is unsubstituted or substituted by one or two identical or different substituents selected from the series consisting of halogen and (Ci-C 4 )-alkyl-O-; and all stereoisomeric forms thereof and mixtures of stereoisomeric forms in any ratio, and the pharmaceutically acceptable salts thereof.
- compounds of the formula I are defined as above and A is a residue selected from the series consisting of R 11 -O-C(O)- and Het 1 , in another embodiment A is R 11 -O-C(O)-, and in another embodiment A is HO-C(O)-.
- the group Het 1 representing A is any one or more of the groups
- (Ci-C 4 )-alkyl wherein in one embodiment (Ci-C 4 )-alkyl is selected from any one or more of the groups methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl;
- Ci-C 4 )-alkyl-O- wherein in one embodiment (Ci-C 4 )-alkyl-O- is selected from any one or more of the groups methyl-O-, ethyl-O-, propyl-O- and butyl-O-;
- Ar is selected from any one or more of the groups phenyl, pyrrolyl and pyridinyl;
- Ar-C(O)- wherein in one embodiment Ar-C(O)- is phenyl-C(O)-, and in one
- Ar-C(O)- is a chloro-substituted benzoyl group, for example Cl-phenyl-C(O)-;
- Ar-O- wherein in one embodiment Ar-O- is selected from any one or more of the groups pyridinyl-O- and phenyl-O-, and in one embodiment is unsubstituted or substituted, in another embodiment is substituted, for example by one or two halogen substituents, for example chlorine substituents, and in another embodiment Ar-O- is selected from any one or more of the groups pyridinyl-O- and Cl-phenyl-O-;
- di((Ci-C 4 )-alkyl)N- wherein in one embodiment di((Ci-C 4 )-alkyl)N- is selected from any one or more of the groups (methyl) 2 N- and (ethyl) 2 N-;
- Ar-(Ci-C 4 )-alkyl- wherein in one embodiment the group Ar in Ar-(Ci-C 4 )-alkyl- is phenyl and in another embodiment Ar-(Ci-C 4 )-alkyl- is benzyl, and in one
- Ar is unsubstituted or substituted, in another embodiment it is
- Het 3 -S(O)2- wherein in one embodiment Het 3 -S(O)2- is pyrrol id inyl-SO2-;
- Het 2 wherein in one embodiment Het 2 is morpholinyl
- (Ci-C 4 )-alkyl which is substituted by one or more fluorine substituents, wherein in one embodiment such fluorine-substituted (Ci-C 4 )-alkyl is (Ci-C 4 )-perfluoroalkyl and in another embodiment is trifluoromethyl, i.e. F 3 C-;
- (Ci-C 4 )-alkyl-O- which is substituted by one or more fluorine substituents, wherein in one embodiment such fluorine-substituted (Ci-C 4 )-alkyl-O- is (Ci-C 4 )-perfluoroalkyl- O- and in another embodiment is trifluoromethoxy, i.e. F 3 C-O-;
- a benzene ring or a 5- membered to 7-membered cycloalkane ring wherein in one embodiment such a ring is a benzene ring or a cyclopentane or cyclohexane ring, and in another embodiment a benzene ring or a cyclohexane ring, and wherein in one embodiment a benzene ring formed by two groups R 1 , R 2 , R 3 and R 4 is unsubstituted or substituted by one or more, for example one or two, identical or different substituents selected from the series consisting of halogen and (Ci-C 4 )-alkyl, and a cycloalkane ring formed by two groups R 1 , R 2 , R 3 and R 4 is unsubstituted or
- the carbocyclic ring which can be formed by either the groups R 1 and R 2 , or the groups R 2 and R 3 , or the groups R 3 and R 4 , together with the carbon atoms carrying them in one embodiment selected from the series consisting of benzene, cyclopentane and cyclohexane, in another embodiment from the series consisting of benzene and cyclohexane. Since in the case of a cydoalkane ring formed by two groups R 1 , R 2 , R 3 and R 4 the double bond between the two carbon atoms common to both fused rings may be regarded as being contained in both rings, such a
- cydoalkane ring may also be regarded as a cycloalkene ring.
- a carbocyclic ring formed by two groups R 1 , R 2 , R 3 and R 4 is unsubstituted or substituted by one or two identical or different substituents, in another embodiment it is unsubstituted.
- R 1 , R 2 , R 3 and R 4 have any of their meanings, except that two groups R 1 , R 2 , R 3 and R 4 together with the carbon atoms carrying them do not form a carbocyclic ring.
- one of the groups R 1 , R 2 , R 3 and R 4 is hydrogen and the others have any of their specified meanings
- two of the group R 1 , R 2 , R 3 and R 4 are hydrogen and the others have any of their specified meanings.
- R 5 is selected from the series consisting of hydrogen and methyl
- R 5 is hydrogen
- compounds of the formula I are defined as above and R 11 , R 12 , R 13 , R 14 and R 15 are independently of each other selected from the series consisting of hydrogen, methyl and ethyl, in another embodiment from the series consisting of hydrogen and methyl, and in another embodiment they are hydrogen.
- a (C3-C8)-cycloalkyl group representing Z 1 or Z 2 is a (C 4 -Cs)- cycloalkyl group, in another embodiment a (Cs-CsJ-cycloalkyl group, in another embodiment a (C 5 -C 7 )-cycloalkyl group, in another embodiment a (C6-C 7 )-cycloalkyl group, in another embodiment a cyclohexyl group, which are all unsubstituted or substituted as specified.
- the number of substituents in a substituted cycloalkyl group and in a substituted phenyl group representing Z 1 or Z 2 independently of one another is one, two, three or four, in another embodiment it is one, two or three, in another embodiment it is one or two, in another embodiment it is one, in another embodiment it is zero.
- a cycloalkyl group representing Z 1 or Z 2 is unsubstituted.
- the substituents in a substituted cycloalkyl group representing Z 1 or Z 2 are selected from the series consisting of fluorine and (Ci-C 4 )-alkyl, in another embodiment from the series consisting of (Ci-C 4 )-alkyl and (Ci-C 4 )-alkyl-O-, and in another embodiment they are (Ci-C 4 )-alkyl substituents.
- the substituents in a substituted phenyl group representing Z 1 or Z 2 are selected from the series consisting of halogen, (Ci-C 4 )-alkyl and (Ci-C 4 )-alkyl-O-, in another embodiment from the series consisting of halogen and (Ci-C 4 )-alkyl.
- compounds of the formula I are defined as above and one of the groups Z 1 and Z 2 is (C3-C8)-cycloalkyl and the other is selected from the series consisting of hydrogen, (Ci-Cs)-alkyl and (C3-C8)-cycloalkyl, in another embodiment one of the groups Z 1 and Z 2 is (C3-C8)-cycloalkyl and the other is selected from the series consisting of hydrogen, (C3-C8)-cycloalkyl and phenyl, in another embodiment one of the groups Z 1 and Z 2 is (C3-C8)-cycloalkyl and the other is selected from the series consisting of hydrogen and (C3-C8)-cycloalkyl, in another embodiment one of the groups Z 1 and Z 2 is (C3-C8)-cycloalkyl and the other is selected from the series consisting of (C3-C8)-cycloalkyl, in another embodiment one of the groups Z 1 and Z 2 is (C3-C8)-cycloalkyl and the other
- the number of substituents in a substituted group Ar or in a substituted group Het 1 or a substituted groups Het 2 or a substituted group Het 3 is independently of one another one, two or three, in another embodiment it is one or two, in another embodiment it is one, in another embodiment it is zero.
- Ar is phenyl or an aromatic 5-membered or 6-membered, monocyclic heterocycle which comprises one ring heteroatom selected from the series consisting of N, O and S
- Ar is selected from the series consisting of phenyl, pyridinyl and thienyl, in another embodiment from the series consisting of phenyl and pyridinyl, and in the another embodiment Ar is phenyl, wherein all groups are unsubstituted or substituted as specified.
- the substituents in a substituted group Ar are selected from the series consisting of halogen, (Ci-C 4 )- alkyl and (Ci-C 4 )-alkyl-O-, in another embodiment from the series consisting of halogen and (Ci-C 4 )-alkyl.
- Het 2 is a saturated 5-membered or 6-membered, monocyclic heterocycle which comprises one or two identical or different ring heteroatoms selected from the series consisting of N, O and S, in another embodiment from the series consisting of N and O, and in another embodiment Het 2 is selected from the series consisting of pyrrol id inyl, tetrahydropyranyl, piperidinyl and morpholinyl, and in another embodiment Het 2 is morpholinyl. In one embodiment, Het 2 is bonded via a ring carbon atom, in another embodiment via a ring nitrogen atom.
- Het 3 is a saturated 5-membered or 6-membered, monocyclic heterocycle which, besides the ring nitrogen atom via which Het 3 is bonded, comprises zero or one, in another embodiment zero, further ring heteroatom selected from the series consisting of N, O and S, in another embodiment from the series consisting of N and O, and in another embodiment Het 3 is selected from the series consisting of pyrrolidinyl, piperidinyl and morpholinyl, and in another embodiment Het 2 is pyrrolidinyl.
- n is selected from the numbers 0 and 2, in another embodiment n is 2.
- the compound of the formula I is selected from the series consisting of
- substitution pattern in the compounds of the formula I which may be termed as 4H-benzo[1 ,3]dioxines or benzo[1 ,3]dioxanes, for example, and herein are also termed benzodioxanes, is numbered according to lUPAC rules and indicated in the following formula.
- structural elements such as groups, substituents or numbers, for example alkyl, cydoalkyi or Ar groups or the number n, can occur several times in the compounds of the formula I, they are all independent of each other and can in each case have any of the indicated meanings, and they can in each case be identical to or different from any other such element.
- alkyl is to be understood as meaning a residue of a saturated acyclic hydrocarbon which can be linear, i. e. straight-chain, or branched. If not otherwise defined, alkyl has 1 to 4 carbon atoms.
- Examples of (Ci-C 4 )-alkyl are alkyl residues containing 1 , 2, 3 or 4 carbon atoms including methyl, ethyl, propyl, butyl, the n- isomers of these residues, isopropyl, isobutyl, sec-butyl, tert-butyl.
- alkyl group is substituted or occurs as a substituent on another residue, for example in an alkyl-O- residue (alkyloxy residue, alkoxy residue), an alkyl-O-C(O)- residue (alkyloxycarbonyl residue) or an aryl-alkyl- residue.
- (C3-C8)-cycloalkyl is to be understood as meaning a residue of a saturated cyclic hydrocarbon cycle containing from 3 to 8 ring carbon atoms in a monocyclic ring.
- Examples of (C3-C8)-cycloalkyl are cydoalkyi residues containing 3, 4, 5, 6, 7 or 8 ring carbon atoms like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
- 5-membered to 7-membered cycloalkane is to be understood as meaning cyclopentane, cyclohexane or cycloheptane.
- Ar is to be understood as meaning phenyl or a residue of an aromatic, 5- membered or 6-membered, monocyclic hydrocarbon ring, wherein in the said hydrocarbon ring one or two ring carbon atoms are replaced by identical or different ring heteroatoms selected from the series consisting of N, O and S, such as furanyl, pyridinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl and thienyl residues, which are all unsubstituted or substituted by one or more, for example by one, two or three, or by one or two, or by one, identical or
- Het 1 is to be understood as meaning a residue of partially unsaturated or aromatic, 5-membered or 6-membered, monocyclic hydrocarbon ring, wherein one to four ring carbon atoms are replaced by identical or different ring heteroatoms selected from the series consisting of N, O and S, such as furanyl, pyridinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl and thienyl, 1 ,2,4,5-tetrazinyl, 1 ,2,3,4-tetrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5-triazinyl, tetrazolyl, thiadiazolyl, 1 ,2,3-triazolyl and 1 ,2,2,
- Het 2 is to be understood as meaning a residue of a saturated, 4-membered, 5-membered, 6-membered or 7-membered, monocyclic hydrocarbon ring, wherein one or two ring carbon atoms are replaced by identical or different ring heteroatoms selected from the series consisting of N, O and S, such as oxetanyl, azetidinyl, thietanyl, dioxetanyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, 1 ,2-oxathiolanyl, 1 ,3-oxathiolanyl, tetrahydrofuranyl and tetrahydropyranyl, which can be bonded via a ring carbon atom or a ring nitrogen atom, and which is unsubstituted or substituted by one or more, for
- Het 3 is to be understood as meaning a residue of a saturated, 4-membered, 5-membered, 6-membered or 7-membered, monocyclic hydrocarbon ring, which comprises a ring nitrogen atom via which Het 3 is bonded and wherein zero or one further ring carbon atom is replaced by a heteroatom selected from the series consisting of N, O and S, such as azetidinyl, morpholinyl, thiomorpholinyl,
- piperazinyl, piperidinyl, pyrrolidinyl, thiazolidinyl and oxazolidinyl and which is unsubstituted or substituted by one or more, for example by one, two or three, or by one or two, or by one, identical or different substituents selected from the series consisting of fluorine and (Ci-C 4 )-alkyl.
- Alkyl groups can in general, independently of any other substituents which an alkyl groups carries, be unsubstituted or substituted by one or more fluorine substituents, for example by one, two, three, four or five fluorine substituents, or by one, two or three fluorine substituents.
- fluorine-substituted alkyl group can also be perfluoroalkyl groups, i.e. alkyl groups in which all hydrogen atoms are replaced by fluorine atoms.
- fluorine-substituted alkyl groups are -CF 3 , -CHF 2 , -CH 2 F and -CF 2 -CF 3 , of which -CF 3 and -CF 2 -CF 3 are examples of perfluoroalkyl groups.
- an alkyl group in any occurrence, independently of other
- Halogen is fluorine, chlorine, bromine or iodine. In one embodiment, halogen is in any of its occurrences, independently of other occurrences, selected from the series consisting of fluorine, chlorine an bromine, in another embodiment from the series consisting of fluorine and chlorine.
- Optically active carbon atoms present in the compounds of the formula I can independently of each other have R configuration or S configuration.
- the compounds of the formula I can be present in the form of pure enantiomers or pure diastereomers or in the form of mixtures of enantiomers and/or diastereomers in any ratio, for example in the form of racemates.
- the present invention relates to pure enantiomers and mixtures of enantiomers as well as to pure diastereomers and mixtures of diastereomers.
- the invention comprises mixtures of two or of more than two stereoisomers of the formula I, and it comprises all ratios of the stereoisomers in the mixtures.
- the compounds of the formula I can be present as E isomers or Z isomers (or cis isomers or trans isomers)
- the invention relates both to pure E isomers and pure Z isomers and to E/Z (or cis/trans) mixtures in all ratios.
- the invention also comprises all tautomeric forms of the compounds of the formula I.
- Diastereomers including E/Z isomers, can be separated into the individual isomers, for example, by chromatography. Racemates can be separated into the two enantiomers by customary methods, for example by chromatography on chiral phases or by resolution, for example by crystallization of diastereomeric salts obtained with optically active acids or bases. Stereochennically uniform compounds of the formula I can also be obtained by employing stereochennically uniform starting materials or by using stereoselective reactions.
- Such salts of compounds of the formula I containing acidic groups are for example alkali metal salts or alkaline earth metal salts such as sodium salts, potassium salts, magnesium salts and calcium salts, and also salts with pharmaceutically acceptable quaternary ammonium ions such as tetramethylammonium or tetraethylammonium, and acid addition salts with ammonia and pharmaceutically acceptable organic amines, such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine.
- Basic groups contained in the compounds of the formula I form acid addition salts, for example with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids such as formic acid, acetic acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, malonic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid.
- Compounds of the formula I which simultaneously contain a basic group and an acidic group, for example an amino group and a carboxyl group, can also be present as zwitterions (betaines), which are likewise included in the present invention.
- Salts of compounds of the formula I can be obtained by customary methods known to those skilled in the art, for example by combining a compound of the formula I with an inorganic or organic acid or base in a solvent or dispersant, or from other salts by cation exchange or anion exchange.
- the present invention also includes all salts of the compounds of the formula I which, because of low physiologically tolerability, are not directly suitable for use in pharmaceuticals but are suitable, for example, as intermediates for carrying out further chemical modifications of the compounds of the formula I or as starting materials for the preparation of pharmaceutically acceptable salts.
- the invention also includes solvates, derivatives and modifications of the compounds of the formula I, for example prodrugs, protected forms and other pharmaceutically acceptable derivatives.
- the invention relates to prodrugs and protected forms of the compounds of the formula I, which can be converted into compounds of the formula I under physiological conditions.
- Suitable prodrugs for the compounds of the formula I i. e. chemically modified derivatives of the compounds of the formula I having properties which are improved in a desired manner, for example with respect to solubility, bioavailability or duration of action, are known to those skilled in the art. More detailed information relating to prodrugs is found in standard literature like, for example, Design of Prodrugs, H.
- Bundgaard (ed.), Elsevier, 1985; Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 1 15-130; H. Bundgaard, Drugs of the Future 16 (1991 ) 443; Hydrolysis in Drug and Prodrug Metabolism, B. Testa, J. M. Mayer, Wiley-VCH, 2003.
- Suitable prodrugs for the compounds of the formula I are especially acyl prodrugs and carbamate prodrugs of acylatable nitrogen-containing groups such as amino groups and ester prodrugs and amide prodrugs of carboxylic acid groups which may be present in compounds of the formula I.
- acyl prodrugs and carbamate prodrugs a hydrogen atom on a nitrogen atom in such groups is replaced with an acyl group or an ester group, for example a (Ci-C6)-alkyl-O-C(O)- group.
- Suitable acyl groups and ester groups for acyl prodrugs and carbamate prodrugs are, for example, the groups R p1 -CO- and R p2 O-CO-, wherein R p1 can be hydrogen, (Ci-C 4 )-alkyl, (C 3 - C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkyl-(Ci-C 4 )-alkyl-, Ar, (C 6 -Ci 4 )-aryl, Het 1 , Het 2 , (C 6 -Ci 4 )- aryl-(Ci-C 4 )-alkyl-, Ar-(Ci-C 4 )-alkyl-, Het 1 -(Ci-C 4 )-alkyl-, Het 2 -(Ci-C 4 )-alkyl- or Het 3 - (Ci-C 4 )-alkyl-, for example, and wherein R
- (C6-Ci 4 )-aryl is understood as meaning a residue of a monocyclic, bicyclic or tricyclic aromatic hydrocarbon containing from 6 to 14 ring carbon atoms, for example 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 ring carbon atoms.
- Examples are phenyl, naphthyl, for example 1 -naphthyl and 2-naphthyl, or biphenylyl.
- the comprised compounds of the formula I are a subject of the invention in all their stereoisomeric forms and mixtures of stereoisomeric forms in any ratio, and in the form of their pharmaceutically acceptable salts, as well as in the form of their prodrugs.
- the present invention also relates to processes for the preparation of the compounds of the formula I, by which the compounds are obtainable and which are another subject of the invention.
- the compounds of the formula I can be prepared by utilizing procedures and techniques, which per se are well known and appreciated by one of ordinary skill in the art. Starting materials or building blocks for use in the general synthetic
- compounds of the formula I can be prepared, for example, in the course of a convergent synthesis, by linking two or more fragments which can be derived retrosynthetically from the formula I. More specifically, suitably substituted starting 2- hydroxymethyl-phenol derivatives are employed as precursor building blocks in the preparation of the benzodioxane compounds of the formula I and reacted with suitably substituted alkanoic acids or alkanoic acid derivatives.
- 2- hydroxymethyl-phenol derivatives of the formula II can be reacted with alkanoic acids or alkanoic acid derivatives of the formula III, which carry two monovalent leaving groups or a divalent oxo group in position 2, such as a 2,2-dichloro-alkanoic acid or derivative thereof like 2,2-dichloro-acetic acid in case the group A' is hydrogen, to give a compound of the formula ⁇ , which can already be the final compound of the formula I or in which further modifications can be made to give the final compound of the formula I.
- the groups X in the compounds of the formula III are suitable monovalent leaving groups, for example halogen like chlorine, or together are an oxygen atom, i.e. form a divalent oxo group, for example.
- 2-hydroxymethyl-phenol derivatives employed in the synthesis of the compound of the formula I can be prepared according to the well-known standard procedures for the formation of 2-hydroxymethyl-phenol systems. By choosing suitable precursor molecules, these 2-hydroxymethyl-phenol syntheses allow the introduction of a variety of substituents into the various positions of the 2-hydroxymethyl-phenol system, which can be chemically modified in order to finally arrive at the compound of the formula I having the desired substituent pattern.
- the groups R 1 , R 2 , R 3 , R 4 , R 5 , Z 1 , Z 2 and A' can be the groups as defined in the formula I, or optionally these residues can be converted into the final groups to give the desired compound of the formula I.
- the residues of the formulae shown above can also be present in the form of groups that can subsequently be transformed into the final groups and. for example, functional groups can be present in the form of precursor groups or of derivatives or in protected form.
- the functional groups introduced into the ring system during the benzodioxane synthesis can be chemically modified.
- a benzodioxane carrying a hydrogen atom in a certain position can also be obtained by saponification and subsequent decarboxylation of a benzodioxane carrying an ester group in that position.
- Halogen atoms can be introduced, for example according to well-known procedures described in the literature.
- the fluorination of aromatic substructures of compounds of the formula I can be carried out using a variety of reagents including, for example, N-fluoro-2,4,6-trimethylpyridinium triflate.
- Chlorinations, brominations, or iodinations can be accomplished by reaction with the elemental halogens or by the use of N-halo-succinimides like NCS, NBS or NIS and many other reagents well known to those skilled in the art. Depending on the reaction conditions, reagent, stoichiometry and substitution pattern, the halogen is introduced in certain positions.
- selective halogen/metal exchange in the obtained compounds like by metalation by selective hydrogen/metal exchange, and subsequent reaction with a wide range of electrophiles various substituents can be introduced at the cyclic nucleus using procedures well-known to those skilled in the art.
- Halogens, hydroxy groups (via the triflate or nonaflate) or primary amines (via the diazonium salt), or after interconversion the corresponding stannanes or boronic acids, present in the benzodioxane structure can be converted into a variety of other functional groups like for example -CN, -CF 3 , -C2F 5 , ethers, acids, amides, amines, alkyl or aryl groups mediated by means of transition metals, such as palladium or nickel catalysts or copper salts and reagents for example referred to below (F.
- nitro groups can be reduced to amino groups with various reducing agents, such as sulfides, dithionites, complex hydrides or by catalytic hydrogenation.
- a reduction of a nitro group may be carried out at various stages of the synthesis of a compound of the formula I, and a reduction of a nitro group to an amino group may also occur simultaneously with a reaction performed on another functional group, for example when reacting a group like a cyano group with hydrogen sulfide or when hydrogenating a group.
- amino groups can then be modified according to standard procedures for alkylation, for example by reaction with (substituted) alkyl halogenides or by reductive amination of carbonyl
- acylation for example by reaction with activated carboxylic acid derivatives such as acid chlorides, anhydrides, activated esters or others or by reaction with carboxylic acids in the presence of an activating agent, or according to standard procedures for sulfonylation, for example by reaction with sulfonyl chlorides.
- Ester groups present in the benzodioxane nucleus can be hydrolyzed to the corresponding carboxylic acids, which after activation can then be reacted with amines or alcohols under standard conditions. Furthermore, these ester or acid groups can be reduced to the corresponding alcohols by many standard procedures.
- Ether groups for example benzyloxy groups or other easily cleavable ether groups, can be cleaved to give hydroxy groups which then can be reacted with a variety of agents, for example etherification agents or activating agents allowing replacement of the hydroxy group by other groups. Sulfur-containing groups can be reacted analogously.
- benzodioxane nucleus can be introduced, for example in the 7-position of the benzodioxane system, for example by standard alkylation procedures well-known to one skilled in the art.
- the starting benzodioxane derivative that is to be employed in such a reaction carries, for example, an oxygen or a nitrogen or a sulfur atom in the 7-position.
- Alkylation of the aforementioned atom can, for example, be performed under standard conditions, preferably in the presence of a base like K2CO3, CS2CO3, NaH or KOtBu, using an alkylating reagent containing a leaving group, like for example halogen like chlorine, bromine or iodine, or a sulfonyloxy group like tosyloxy, mesyloxy or trifluormethylsulfonyloxy.
- a leaving group like for example halogen like chlorine, bromine or iodine
- a sulfonyloxy group like tosyloxy, mesyloxy or trifluormethylsulfonyloxy.
- a leaving group may, for example, also be a hydroxy group which, in order to achieve the alkylation reaction, is activated under the well-known conditions of the Mitsunobu procedure (O.
- the structural elements present in the residues in the 4-position, 5-position, 6- position, 7-position and the 8-position of the benzodioxane ring in the compounds of the formula I can also be introduced, for example into the 2-hydroxymethyl-phenol precursor or the benzodioxane, using the methods outlined herein by consecutive reaction steps using parallel synthesis methodologies using procedures which per se are well known to one skilled in the art.
- Such strategies are well known to those skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, Wiley, 1991 ; or P. Kocienski, Protecting Groups, Thieme, 1994).
- precursor groups are cyano groups and nitro groups.
- the cyano group can, in a later step, be transformed into carboxylic acid derivatives, or by reduction into aminomethyl groups. Nitro groups may be transformed by reduction like catalytic hydrogenation into amino groups.
- Protective groups can also have the meaning of a solid phase, and cleavage from the solid phase stands for the removal of the protective group. The use of such techniques is known to those skilled in the art (Burgess K (Ed.) Solid Phase Organic Synthesis, New York, Wiley, 2000).
- a phenolic hydroxy group can be attached to a trityl-polystyrene resin, which serves as a protecting group, and the molecule is cleaved from this resin by treatment with trifluoroacetic acid (TFA) or other acids at a later stage of the synthesis.
- TFA trifluoroacetic acid
- the compounds of the formula I are effective LPAR5 antagonists which antagonize the effect of endogenous LPA on its LPAR5 receptor.
- LPAR5 antagonists which antagonize the effect of endogenous LPA on its LPAR5 receptor.
- the compounds of the formula I effective platelet, mast cell and microglial cell LPA receptor LPAR5 antagonists.
- the compounds of the invention antagonize the platelet aggregating effect of the activation of the platelet LPA receptor LPAR5, the LPA- mediated activation of human mast cells and the LPA-mediated activation of microglia cells.
- the compounds of the formula I of the invention also have further advantageous properties, for instance stability in plasma and liver and selectivity versus other receptors whose agonism or antagonism is not intended. This good selectivity, for example, makes it possible to reduce potential side effects existing with regard to molecules having inadequate selectivity.
- a subject of the present invention also are the compounds of the formula I and/or the pharmaceutically acceptable salts thereof and/or prodrugs thereof for use as a medicament or as a pharmaceutical, and pharmaceutical compositions which comprise an effective amount of at least one compound of the formula I and/or a pharmaceutical acceptable salt thereof and/or a prodrug thereof and a
- pharmaceutically acceptable carrier i.e. one or more pharmaceutically acceptable carrier substances or excipients and/or auxiliary substances or additives, and can be employed in human, veterinary or phytoprotective use.
- the activity of the compounds of the formula I can be determined, for example, in the assays described below or in other in vitro or ex vivo assays known to those skilled in the art.
- the ability of the compounds to inhibit LPA-induced aggregation of platelets may be measured by methods similar to those described in the literature (for example, Holub and Waston in Platelets: A Practical Approach, pp 236-239, Oxford University Press 1996), and by the methods described below.
- the compounds of the invention are functional antagonists of the platelet LPA receptor LPAR5 and are therefore useful for inhibiting platelet aggregation and thrombus formation.
- the ability of the compounds to inhibit LPA-induced activation of mast cells or microglial cells may also be measured by using the FLIPR system.
- the compounds of the formula I and/or their pharmaceutically acceptable salts and/or their prodrugs are generally suitable for the treatment, including therapy and prophylaxis, of conditions in which the activity of LPAR5 receptor plays a role or has an undesired extent, or which can favorably be influenced by inhibiting LPAR5 receptors or decreasing the activity, or for the prevention, alleviation or cure of which an inhibition of LPA receptor LPAR5 or a decrease in the activity is desired by the physician.
- a subject of the invention also are the compounds of the formula I and/or the pharmaceutically acceptable salts thereof and/or the prodrugs thereof for the use in the treatment, including therapy and prophylaxis, of a disease or disease state responsive to the inhibition of the LPA receptor LPAR5 and/or the reduction or inhibition of platelet aggregation or thrombus formation and/or the reduction or inhibition of the activation of mast cells and/or the reduction or inhibition of the activation of microglial cells.
- a subject of the invention also is the use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof and/or the prodrugs thereof for the manufacture of a medicament for the treatment, including therapy and prophylaxis, of a disease or disease state responsive to the inhibition of the LPA receptor LPAR5 and/or the reduction or inhibition of platelet aggregation or thrombus formation and/or the reduction or inhibition of the activation of mast cells and/or the reduction or inhibition of the activation of microglial cells.
- a subject of the invention also are the specific compounds of the formula I which are excluded from the compounds which are a subject of the invention as compounds per se, i. e. 6-chloro-4-cyclohexyl-4-phenyl-4H-benzo[1 ,3]dioxine-2-carboxylic acid, 6-chloro-4-cyclohexyl-4-phenyl-4H-benzo[1 ,3]dioxine-2-carboxylic acid methyl ester and 6-chloro-4,4-dicyclohexyl-4H-benzo[1 ,3]dioxine-2-carboxylic acid, and the pharmaceutically acceptable salts thereof and the prodrugs thereof, for the use in the treatment, including therapy and prophylaxis, of a disease or disease state
- a subject of the invention also is the use of the compounds of the formula I which are excluded from the compounds which are a subject of the invention as compounds per se, i. e.
- 6-chloro-4-cyclohexyl-4-phenyl-4H-benzo[1 ,3]dioxine-2-carboxylic acid 6-chloro-4-cyclohexyl-4-phenyl-4H-benzo[1 ,3]dioxine-2-carboxylic acid methyl ester and 6-chloro-4,4-dicyclohexyl-4H-benzo[1 ,3]dioxine-2-carboxylic acid, and the pharmaceutically acceptable salts thereof and the prodrugs thereof, for the
- manufacture of a medicament for the treatment including therapy and prophylaxis, of a disease or disease state responsive to the inhibition of the LPA receptor LPAR5 and/or the reduction or inhibition of platelet aggregation or thrombus formation and/or the reduction or inhibition of activation of mast cells and/or the reduction or inhibition of activation of microglial cells, and all other diseases mentioned above or below herein.
- the compounds of the formula I and/or their pharmaceutically As inhibition of the LPA receptor LPAR5 influences platelet activation and platelet aggregation, the compounds of the formula I and/or their pharmaceutically
- acceptable salts and/or their prodrugs are generally suitable for reducing blood thrombus formation, or for the treatment, including therapy and prophylaxis, of conditions and diseases in which the activity of the platelet aggregation plays a role or has an undesired extent, or which can favorably be influenced by reducing thrombus formation, or for the prevention, alleviation or cure of which a decreased activity of the platelet aggregation system is desired by the physician.
- a specific subject of the present invention thus is the reduction or inhibition of unwanted thrombus formation, in particular in an individual, by administering an effective amount of a compound of the formula I and/or a pharmaceutically acceptable salt and/or a prodrug thereof, as well as pharmaceutical compositions therefore.
- compounds of the formula I and/or their pharmaceutically acceptable salts and/or their prodrugs are generally suitable for reducing mast cell activation, or for the treatment, including therapy and prophylaxis, of conditions in which the activity mast cells plays a role or has an undesired extent, or which can favorably be influenced by reducing mast cell activation, or for the prevention, alleviation or cure of which a decreased activity of the mast cell system is desired by the physician.
- a specific subject of the present invention thus is the reduction or inhibition of unwanted activation of mast cells, in particular in an individual, by administering an effective amount of a compound of the formula I and/or a pharmaceutically acceptable salt and/or a prodrug thereof, as well as pharmaceutical compositions therefore.
- the compounds of the formula I and/or their pharmaceutically acceptable salts and/or their prodrugs are generally suitable for reducing microglial cell activation, or for the treatment, including therapy and prophylaxiss of conditions in which the activity of microglial cells plays a role or has an undesired extent, or which can favorably be influenced by reducing microglial cell activation, or for the prevention, alleviation or cure of which a decreased activity of the microglial cell system is desired by the physician.
- a specific subject of the present invention thus is the reduction or inhibition of unwanted activation of microglial cell, in particular in an individual, by
- the present invention also relates to the compounds of the formula I and/or their pharmaceutically acceptable salts and/or their prodrugs for the use in the treatment, including therapy and prophylaxis, of thromboembolic diseases, such as deep vein thrombosis, venous and arterial thromboembolism, thrombophlebitis, coronary and cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, disseminated intravascular coagulation, cardiovascular disorders, such as transient ischemic attacks, strokes, acute myocardial infarction, peripheral vascular disease, preeclampsia/eclampsia, and thrombotic cytopenic purpura and
- thromboembolic diseases such as deep vein thrombosis, venous and arterial thromboembolism, thrombophlebitis, coronary and cerebral arterial thrombosis, cerebral embolism, renal embolism, pulmonary embolism, disseminated intravascular
- inflammatory disorders such as hyperalgesia, asthma, multiple sclerosis, inflammatory pain, angiogenesis or allergic responses, or restenoses.
- the present invention also relates to the use of the compounds of the formula I and/or their pharmaceutically acceptable salts and/or their prodrugs for the
- the invention also relates to the compounds of the formula I and/or their
- pharmaceutically acceptable salts and/or their prodrugs for the use in the treatment, including therapy and prophylaxis, of the diseases mentioned above or below, for example for use in the therapy and prophylaxis of cardiovascular disorders, thromboembolic diseases or restenoses, and to methods of treatment aiming at such purposes including methods for said therapies and prophylaxis.
- the invention also relates to compounds of the formula I and/or the pharmaceutically acceptable salts thereof for the use in the treatment, including therapy and prophylaxis, of disease states such as abnormal thrombus formation, acute myocardial infarction, thromboembolism, acute vessel closure associated with thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication, bypass grafting of the coronary or peripheral arteries, vessel luminal narrowing, restenosis post coronary or venous angioplasty, maintenance of vascular access patency in long-term
- disease states such as abnormal thrombus formation, acute myocardial infarction, thromboembolism, acute vessel closure associated with thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication, bypass grafting of the coronary or peripheral arteries, vessel luminal narrowing, restenosis post coronary or venous angioplasty
- the invention also relates to the use of a compound of the formula I and/or the
- the invention also relates to compounds of the formula I and/or the pharmaceutically acceptable salts thereof for the use in the treatment, including therapy and prophylaxis, of disease states such as inflammatory pain, asthma, angiogenesis, demyelating diseases of (a) the central nervous system, such as multiple sclerosis, transverse myelitis, optic neuritis, Devic's disease, and (b) the peripheral nervous system, such as Guillain-Barre syndrome or chronic inflammatory demyelinating polyneuropathy, as well as to the use of a compound of the formula I and/or the pharmaceutically acceptable salts thereof for the
- manufacture of a medicament for the treatment including therapy and prophylaxis, of said disease states.
- the compounds of the formula I and their pharmaceutically acceptable salts and their prodrugs can be administered to animals, preferably to mammals, and in particular to humans as pharmaceuticals for therapy or prophylaxis. They can be administered alone, or in mixtures with one another or in the form of pharmaceutical compositions, which permit enteral or parenteral administration.
- compositions according to the invention can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatine capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. Administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions,
- microcapsules implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
- compositions according to the invention are prepared in a manner known per se and familiar to one skilled in the art, pharmaceutically acceptable inert inorganic and/or organic carrier substances and/or auxiliary substances being used in addition to one or more compounds of the formula I and/or their pharmaceutically acceptable salts and/or their prodrugs.
- pharmaceutically acceptable inert inorganic and/or organic carrier substances and/or auxiliary substances being used in addition to one or more compounds of the formula I and/or their pharmaceutically acceptable salts and/or their prodrugs.
- pharmaceutically acceptable inert inorganic and/or organic carrier substances and/or auxiliary substances being used in addition to one or more compounds of the formula I and/or their pharmaceutically acceptable salts and/or their prodrugs.
- pharmaceutically acceptable inert inorganic and/or organic carrier substances and/or auxiliary substances being used in addition to one or more compounds of the formula I and/or their pharmaceutically acceptable salts and/or their prodrugs.
- Carrier substances for soft gelatine capsules and suppositories are
- Suitable carrier substances for the production of solutions for example injection solutions, or of emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc.
- Suitable carrier substances for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.
- the pharmaceutical compositions normally contain about 0.5 % to about 90 % by weight of the compounds of the formula I and/or their pharmaceutically acceptable salts and/or their prodrugs.
- the amount of the active ingredient of the formula I and/or its pharmaceutically acceptable salts and/or its prodrugs in the pharmaceutical compositions normally is from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg.
- the pharmaceutical compositions can contain auxiliary substances or additives such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula I, and/or their pharmaceutically acceptable salts and/or their prodrugs. In case a pharmaceutical composition contains two or more compounds of the formula I, the selection of the individual compounds can aim at a specific overall pharmacological profile of the
- compositions for example, a highly potent compound with a shorter duration of action may be combined with a long-acting compound of lower potency.
- the flexibility permitted with respect to the choice of substituents in the compounds of the formula I allows a great deal of control over the biological and physico- chemical properties of the compounds and thus allows the selection of such desired compounds.
- the pharmaceutical compositions can also contain one or more other pharmaceutically, therapeutically and/or prophylactically active ingredients.
- the dose can vary within wide limits and, as is customary and is known to the physician, is to be suited to the individual conditions in each individual case. It depends, for example, on the specific compound employed, on the nature and severity of the disease to be treated, on the mode and the schedule of administration, or on whether an acute or chronic condition is treated or whether prophylaxis is carried out.
- An appropriate dosage can be established using clinical approaches well known in the medical art.
- the daily dose for achieving the desired results in an adult weighing about 75 kg is from 0.01 mg/kg to 100 mg/kg, preferably from 0.1 mg/kg to 50 mg/kg, in particular from 0.1 mg/kg to 10 mg/kg, (in each case in mg per kg of body weight).
- the daily dose can be divided, in particular in the case of the administration of relatively large amounts, into several, for example 2, 3 or 4, part administrations. As usual, depending on individual behavior it may be necessary to deviate upwards or downwards from the daily dose indicated.
- the compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of the LPA receptor LPAR5.
- Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving the LPA receptor LPAR5.
- a compound of the present invention can be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound.
- compounds according to the present invention can be used to test their effectiveness.
- a compound of the formula I can also advantageously be used as an antiaggregant outside an individual.
- an effective amount of a compound of the invention can be contacted with a freshly drawn blood sample to prevent aggregation of the blood sample.
- a compound of the formula I or its salts can be used for diagnostic purposes, for example in in vitro diagnoses, and as an auxiliary in biochemical investigations.
- a compound of the formula I can be used in an assay to identify the presence of the LPA receptor LPAR5 or to isolate the LPA receptor LPAR5 containing tissue in a substantially purified form.
- a compound of the invention can be labeled with, for example, a radioisotope, and the labeled
- a compound of the formula I or a salt thereof can be used as a probe to detect the location or amount of LPAR5 activity in vivo, in vitro or ex vivo.
- the compounds of the formula I can be used as synthesis intermediates for the preparation of other compounds, in particular of other pharmaceutical active ingredients, which are obtainable from the compounds of the formula I, for example by introduction of substituents or modification of functional groups.
- the general synthetic sequences for preparing the compounds useful in the present invention are outlined in detail in the examples given below which are intended to be merely illustrative of the present invention and not limiting it in either scope or spirit. Those with skill in the art will readily understand that known variations of the conditions and processes described in the examples can be used to synthesize the compounds of the present invention.
- an acid such as trifluoroacetic acid or acetic acid was used, for example when trifluoroacetic acid was employed to an acid-labile protecting group (for example a tBu group) or when a compound was purified by chromatography using an eluent which contained such an acid, in some cases, depending on the work-up procedure, for example the details of a freeze- drying process, the compound was obtained partially or completely in the form of a salt of the acid used, for example in the form of the acetic acid salt, formic acid salt or trifluoroacetic acid salt or hydrochloric acid salt.
- an acid such as trifluoroacetic acid or acetic acid was used, for example when trifluoroacetic acid was employed to an acid-labile protecting group (for example a tBu group) or when a compound was purified by chromatography using an eluent which contained such an acid, in some cases, depending on the work-up procedure, for example the details of a freeze- drying process, the compound was
- starting materials or intermediates bearing a basic center like, for example, a basic nitrogen were either obtained and used as free base or in salt form like, for example, a trifluoroacetic acid salt, a hydrobromic acid salt, a sulfuric acid salt, or a hydrochloric acid salt.
- Room temperature means a temperature of about 20 °C to 25 °C.
- reaction mixture was heated to 60 °C and a solution of 504 mg of 2-(Dicyclohexyl-hydroxy-methyl)-5-pyrrol-1 -yl-phenol in 6 mL anhydrous dioxane was added and stirred at 95 °C for 6 h. After cooling to 0°C, the reaction mixture was quenched with 2 ml of isopropanol and poured on ice. The aqueous phase was extracted with ether, then acidified with HCI (2 M, to pH 1 ), and extracted with ethyl acetate. The combined organic layers were dried over MgSO 4 , filtered and
- Example 1 7-Chloro-4,4-dicyclohexyl-4H-benzo[1 ,3]dioxine-2-carboxylic acid
- Example 33 1 ,1 -Dicyclohexyl-1 H-naphtho[2,1 -d][1 ,3]dioxine-3-carboxylic acid
- the ability of the compounds of the formula I to inhibit or bind the LPA receptor LPAR5 can be assessed by determining the effect on cellular function. This ability of such compounds was evaluated in a platelet aggregation assay such as the Born method using single cuvettes and for mast cells and microglia cells with the
- Fluorometric Imaging Plate Reader FLIPR assay by Molecular Devices Inc.
- the PRP phase was transferred to a new 50ml tube. After 10 minutes standing at room temperature, 1 ⁇ PGI 2 (1 mM in Tris-HCI / pH 8.8) and 180 ⁇ ACD/A were added per ml PRP. The PRP was then transferred to new 10ml tube and centrifuged for 10 minutes at 500 x g. After centrifugation a cellular pellet is visible at the bottom of the tube. The supernatant was carefully discarded and the cellular pellet, consisting of human blood platelets was then dissolved in 10ml buffer T (buffer T composition: 145mM NaCI, 5mM KCI, 0.1 mM MgCI 2 x 6 H 2 O, 15mM HEPES, 5.5mM glucose, pH 7.4). Platelet concentration in this solution was determined and buffer T was added to obtain a final concentration of 3.5 X 10 5 platelets per ml.
- buffer T composition buffer T composition: 145mM NaCI, 5mM KCI, 0.1 mM MgCI 2
- FLIPR Fluorometric Imaging Plate Reader
- the ability of the compounds of the formula I to inhibit or bind the LPA receptor LPAR5 can be assessed by determining the intracellular Ca 2+ release in human or animal cells.
- two cell lines were used with high LPAR5 expression, the human mast cell line HMC-1 and the murine microglia cell line BV-2 ( Figure 1 and 2).
- HMC-1 suspension cells from flask culture were harvested, resuspended and counted. 14 x 10 6 HMC-1 cells were transferred into a new 50ml tube, centrifuged for 3 minutes at 540 x g.
- loading buffer contained HBSS buffer (pH 7.4), 0.1 % BSA (bovine serum albumin), 2 ⁇ FLUO-4 dye; HBSS buffer (pH 7.4) contained 1 x HBSS, 20mM HEPES, 0.01 % Pluronic F-127, 2.5mM Probenicid).
- IC 5 o data of the above described FLIPR assay using human mast cell line HMC-1 for exemplary compounds of the present invention are shown in Table 2.
- Adherent BV-2 cells were seeded onto poly-D-lysine coated 96-well-plates (100000 cells / well) the day before performing the FLIPR assay. The density of the cells in the 96-well-plate at the day of the FLIPR assay should be 90%. After aspiration of the culture media, BV-2 cells were incubated for 30 minutes at 37°C with loading buffer and recovered in 150 ⁇ HBSS buffer for 30 minutes at 37°C.
- Example IC50 ( ⁇ ) Example IC50 ( ⁇ )
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Abstract
Description
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CN201380025938.2A CN104302633B (en) | 2012-05-18 | 2013-05-16 | Benzo [1,3] dioxine derivative and they are as the application of LPAR5 antagonist |
ES13723767.3T ES2649438T3 (en) | 2012-05-18 | 2013-05-16 | Benzo [1,3] dioxin derivatives and their use as antagonists of LPAR5 |
KR20147033844A KR20150016304A (en) | 2012-05-18 | 2013-05-16 | Benzo[1,3]dioxine derivatives and their use as lpar5 antagonists |
BR112014028189A BR112014028189A2 (en) | 2012-05-18 | 2013-05-16 | benzo [1,3] dioxin derivatives and their use as lpar5 antagonists |
SG11201407216YA SG11201407216YA (en) | 2012-05-18 | 2013-05-16 | Benzo[1,3]dioxine derivatives and their use as lpar5 antagonists |
CA 2871545 CA2871545A1 (en) | 2012-05-18 | 2013-05-16 | Benzo[1,3]dioxine derivatives and their use as lpar5 antagonists |
EP13723767.3A EP2850070B1 (en) | 2012-05-18 | 2013-05-16 | Benzo[1,3]dioxine derivatives and their use as lpar5 antagonists |
MX2014014012A MX354521B (en) | 2012-05-18 | 2013-05-16 | Benzo[1,3]dioxine derivatives and their use as lpar5 antagonists. |
PL13723767T PL2850070T3 (en) | 2012-05-18 | 2013-05-16 | Benzo[1,3]dioxine derivatives and their use as lpar5 antagonists |
RU2014151240A RU2647727C2 (en) | 2012-05-18 | 2013-05-16 | Benzo[1,3]dioxin derivatives and their use as lpar5 antagonists |
AU2013261719A AU2013261719B2 (en) | 2012-05-18 | 2013-05-16 | Benzo[1,3]dioxine derivatives and their use as LPAR5 antagonists |
US14/401,041 US9221784B2 (en) | 2012-05-18 | 2013-05-16 | Benzo[1,3]dioxine derivatives and their use as LPAR5 antagonists |
SI201330853T SI2850070T1 (en) | 2012-05-18 | 2013-05-16 | Benzo(1,3)dioxine derivatives and their use as lpar5 antagonists |
JP2015512073A JP6238970B2 (en) | 2012-05-18 | 2013-05-16 | Benzo [1,3] dioxin derivatives and their use as LPAR5 antagonists |
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GB2022579A (en) | 1978-05-03 | 1979-12-19 | Roussel Uclaf | 4h-1,3-benzodioxin-2-carboxylic acid derivatives |
WO2005000284A2 (en) * | 2003-05-20 | 2005-01-06 | Bayer Pharmaceuticals Corporation | Diaryl ureas for diseases mediated by pdgfr |
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US4056450A (en) | 1975-06-30 | 1977-11-01 | M & T Chemicals Inc. | Continuous detinning system |
FR2424914A2 (en) * | 1978-05-03 | 1979-11-30 | Roussel Uclaf | NEW DERIVATIVES OF (1-3) BENZODIOXIN, A PROCESS FOR THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
GB8310407D0 (en) * | 1982-05-12 | 1983-05-25 | Ici Plc | 1 3 - dioxan -5- ylalkenoic acids |
FR2704857B1 (en) * | 1993-05-07 | 1995-06-23 | Adir | New substituted benzodioxins, process for their preparation and pharmaceutical compositions containing them. |
ES2365024T3 (en) * | 2004-05-07 | 2011-09-20 | Memory Pharmaceuticals Corporation | 1H-INDAZOLES, BENZOTIAZOLES, 1,2-BENZOISOXAZOLES, 1,2-BENZOISOTIAZOLES AND CHROMONES, AND PREPARATION AND USES OF THE SAME. |
WO2010042600A2 (en) * | 2008-10-08 | 2010-04-15 | The Uab Research Foundation | Photo-activatable therapeutic agents and methods of using |
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ES2649438T3 (en) | 2018-01-12 |
CN104302633A (en) | 2015-01-21 |
AU2013261719B2 (en) | 2017-07-27 |
MX354521B (en) | 2018-03-08 |
SG11201407216YA (en) | 2014-12-30 |
EP2850070A1 (en) | 2015-03-25 |
JP2015517515A (en) | 2015-06-22 |
IL235219A (en) | 2017-03-30 |
US9221784B2 (en) | 2015-12-29 |
CN104302633B (en) | 2016-09-07 |
EP2850070B1 (en) | 2017-08-23 |
US20150111889A1 (en) | 2015-04-23 |
JP6238970B2 (en) | 2017-11-29 |
RU2014151240A (en) | 2016-07-10 |
BR112014028189A2 (en) | 2017-06-27 |
KR20150016304A (en) | 2015-02-11 |
MX2014014012A (en) | 2015-02-12 |
AU2013261719A1 (en) | 2014-12-18 |
RU2647727C2 (en) | 2018-03-19 |
CA2871545A1 (en) | 2013-11-21 |
SI2850070T1 (en) | 2018-01-31 |
PL2850070T3 (en) | 2018-01-31 |
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