EP2079699A1 - Chinolinderivate - Google Patents

Chinolinderivate

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Publication number
EP2079699A1
EP2079699A1 EP07815779A EP07815779A EP2079699A1 EP 2079699 A1 EP2079699 A1 EP 2079699A1 EP 07815779 A EP07815779 A EP 07815779A EP 07815779 A EP07815779 A EP 07815779A EP 2079699 A1 EP2079699 A1 EP 2079699A1
Authority
EP
European Patent Office
Prior art keywords
methyl
hydroxyquinolin
chloro
pyridin
acetamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07815779A
Other languages
English (en)
French (fr)
Inventor
Siegfried Hekimi
Kevin Mcbride
Abdelmadjid K. Hihi
Irenej Kianicka
Ying Wang
Steven Leonard Hayes
Marie-Pierre Guimond
Guy SÉVIGNY
Daniel Dumas
Julian Smith
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Forum Pharmaceuticals Inc
Original Assignee
EnVivo Phamaceuticals Inc
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Filing date
Publication date
Application filed by EnVivo Phamaceuticals Inc filed Critical EnVivo Phamaceuticals Inc
Publication of EP2079699A1 publication Critical patent/EP2079699A1/de
Withdrawn legal-status Critical Current

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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • the present invention relates to new quinoline derivatives as CLK-1 inhibitors. More specifically, the present invention relates to new quinoline derivatives or their pharmaceutically acceptable salts or pro-drugs as CLK-1 inhibitors, and to pharmaceutical compositions comprising the same and to methods for the prophylaxis and/or treatment of disorders or its associated symptoms for which the inhibition of CLK-1 is beneficial.
  • the clk-1 gene encodes a 21 kDa mitochondrial protein which is conserved amongst eukaryotes with sequence identity of 85% between mouse and human sequence and 50% with the homologous sequence of the nematode worm Caenorhabditis elegans.
  • CLK-1 participates in one of the last steps of ubiquinone biosynthesis and is responsible for demethoxyubiquinone (DMQ) hydroxylation. Mutants in which CLK-1 is inactive do not synthesize detectable amounts of ubiquinone (Q), and rather accumulate DMQ (Miyadera et al. 2001).
  • Q has numerous functions in the cell. It is involved in electron transport in the inner mitochondrial membrane, the plasma membrane, and the membrane of the lysosome. It is also a cofactor for several cellular enzymes (e.g. dihydroorotate dehydrogenase, which is necessary for nucleic acid biosynthesis) and other proteins and complexes such as the mitochondrial uncoupling proteins (UCP) which regulate metabolic heat production and the mitochondrial permeability transition pore (MPTP) which regulates programmed cell death.
  • dihydroorotate dehydrogenase which is necessary for nucleic acid biosynthesis
  • UCP mitochondrial uncoupling proteins
  • MPTP mitochondrial permeability transition pore
  • DMQ is a quinone that can transport electrons, although less efficiently than ubiquinone.
  • Mouse embryos in which the clk-1 homologue (mclk-1) has been knocked out also accumulate DMQ, and are not viable (Levavasseur et al. 2001) but mice heterozygous for mclk-1 display an increased lifespan phenotype.
  • Transgenic expression of CLK-1 in the mouse knock-out rescues the lethality phenotype, and allows ubiquinone synthesis (Nakai et al. 2004).
  • heterologous expression of C is a quinone that can transport electrons, although less efficiently than ubiquinone.
  • Lifespan is a cumulative phenotype that integrates variations in worm physiology, and that is sensitive to environmental cues, and to genetic mutations. As such, conditions that extend lifespan are often considered as beneficial. For example, a favourable repair vs. damage balance would manifest itself by increasing lifespan (Hekimi et al. 2001).
  • Age-related diseases refer to diseases for which the incidence and/or prevalence increase with age. These diseases include by example, cancers, cerebrovascular disease (stroke), neurodegenerative diseases, pneumonia, respiratory diseases, arthritis, heart diseases, diabetes, hearing impairment, vision impairment and kidney disease.
  • stroke cerebrovascular disease
  • neurodegenerative diseases pneumonia, respiratory diseases, arthritis, heart diseases, diabetes, hearing impairment, vision impairment and kidney disease.
  • quinoline derivatives are disclosed in CA 2.493.536 A1 , US 2006/0074104 A1 and WO 2004/087160 A1 for use in the treatment, amelioration and/or prophylaxis of neurological conditions in particular those associated with or facilitated by oxidative stress.
  • the neurological disorders contemplated include any condition leading to cognitive impairment such as pre- or mild cognitive impairment or memory loss.
  • the present inventors have developed a new family of compounds which are active to inhibit CLK-1. Such compounds are active on age-related disorders as well as on ischemia-reperfusion injury and inflammation disorders.
  • an object of the present invention is to provide new quinoline derivatives of formula A, which have CLK-1 inhibitory activity.
  • the present invention relates to the compounds of formula A as defined below, or their pharmaceutically acceptable salts or their pro-drugs:
  • R 2 when R 2 is hydrogen, then Ri is H or halogen, or R 1 is selected from the group consisting of: amino(3,4-dimethoxyphenyl)methyl, 2-hydroxyphenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 4-dimethylaminophenyl, pyridin-4-yl, 2- methoxypyridin-3-yl and 2-acetamidophenyl;
  • Re is selected from the group consiting of: C 1 -Ce alkyl, Cs-C ⁇ aryl, benzyl, dimethylaminomethyl, phenylethyl and diphenylmethyl; and ⁇ R 3 is selected from the group consisting of:
  • Ri is — c — N — R 7 and R 7 is -(ChMn-Rs where Rs is a Cs-C ⁇ aryl optionally
  • R 2 is selected from the group consisting of: pyridin-2-ylcarboxamido, pyridin-2-ylacetamido, 3- hydroxyphenylacetamido, 4-hydroxyphenylacetamido, ((2- methoxyphenyl)amino)methyl, ((3-methoxyphenyl)amino)methyl, ((3- methoxybenzyl)amino)methyl, 2-thienylacetamido and ((2- thienylmethyl)amino)methyl;
  • each of the compounds of formula A is not one of the compounds identified in Annex 1.
  • the compounds of Formula A of the invention when comprising at least one asymmetric centre are either in the form of one of their optically active isomers like enantiomers or a mixture thereof including for example the racemate.
  • the invention also relates to a method for inhibiting CLK-1 activity in a cell which comprises the following steps: a) providing a cell wherein CLK-1 activity needs to be inhibited, b) contacting the cell with a compound of formula (B) as defined below, or a pharmaceutically acceptable salts or a pro-drug thereof:
  • the invention also relates to a method for the prophylaxis and/or treatment of a disorder or its associated symptoms for which inhibition of CLK-1 is beneficial, in animal, which comprises the following steps: a) identifying an animal having a disorder for which inhibition of CLK-1 is beneficial; and b) administering to the animal a compound of formula (B), a pharmaceutically acceptable salts or a pro-drug thereof.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula A of the invention, a pharmaceutically acceptable salt or a pro-drug thereof, and at least one pharmaceutically acceptable carrier.
  • the invention further relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula A or B as defined hereinabove, a pharmaceutically acceptable salt or a pro-drug thereof, and at least one pharmaceutically acceptable carrier, to effectively reduce and/or inhibit totally or partially CLK-1 activity.
  • FIGURES Figure 1 HPLC profiles showing the induction of DMQ in quinone profiles after treatment with a CLK-1 inhibitor.
  • Mouse macrophages (RAW264.7) were treated with a) an inactive compound or b) the active compound 135 (1 ⁇ M) for 24hr, followed by cell lysis and hexane/ethanol extraction of quinones. Samples were run with methanol/ethanol gradients on HPLC with UV detection to determine levels of ubiquinone (Q) and its precursor, demethoxyubiquinone (DMQ).
  • Q ubiquinone
  • DMQ demethoxyubiquinone
  • Figure 2 HPLC profiles showing relative quinone peaks in RAW264.7 cells treated with a) DMSO or b) 10 ⁇ M of Compound 7 (Q: Ubiquinone, DMQ: Demethoxyubiquinone).
  • Figure 3 HPLC profiles showing relative quinone peaks in RAW264.7 cells treated with a) 1 ⁇ M or b) 3 ⁇ M of Compound 23 (Q: Ubiquinone, DMQ: Demethoxyubiquinone).
  • Figure 4 HPLC profiles showing relative quinone peaks in RAW264.7 cells treated with a) 5 ⁇ M or b) 10 ⁇ M of Compound 69 (Q: Ubiquinone, DMQ: Demethoxyubiquinone).
  • Figure 5 HPLC profiles showing relative quinone peaks in RAW264.7 cells treated with a) 5 ⁇ M or b) 10 ⁇ M of Compound 47 (Q: Ubiquinone, DMQ: Demethoxyubiquinone).
  • Figure 6 HPLC profiles showing relative quinone peaks in RAW264.7 cells treated with a) 5 ⁇ M or b) 10 ⁇ M of Compound 53 (Q: Ubiquinone, DMQ: Demethoxyubiquinone).
  • Figure 7 Specificity of CLK-1 inhibitor. Effect of Compound 7 on a) mouse CLK-1 (JF496-A77c//c7 testing system), and b) the bacterial DMQ hydroxylase UbiF (JF496-ub/F testing system). JF496 bacteria expressing a) mouse CLK-1 and b) the bacterial DMQ-hydroxylase UbiF were treated with Compound 7 for 5h. Quinones were extracted and analyzed using HPLC.
  • the HPLC trace shows that CLK-1 activity is inhibited by 7, as ubiquinone (Q) synthesis is lowered with a concomitant increase of demethoxyubiquinone (DMQ). In contrast to that, UbiF activity is not affected, and Q is the major quinone species detected. This shows that Compound 7 has a specific CLK-1 inhibition activity.
  • Figure 8 Specificity of CLK-1 inhibitor. Effect of Compound 52 on a) mouse CLK- 1 (JF496-/77C//C/ testing system), and b) the bacterial DMQ hydroxylase UbiF (JF496-t/b/F testing system). JF496 bacteria expressing a) mouse CLK-1 and b) the bacterial DMQ-hydroxylase UbiF were treated with Compound 52 for 5hrs. Quinones were extracted and analyzed using HPLC. The HPLC trace shows that CLK-1 activity is inhibited by 52, as ubiquinone (Q) synthesis is lowered with a concomitant increase of demethoxyubiquinone (DMQ). In contrast to that, UbiF activity is not affected, and Q is the major quinone species detected. This shows that Compound 52 has a CLK-1 -specific inhibition activity.
  • FIG. 9 ROS lowering effect of CLK-1 inhibitors (7 and 135).
  • A table showing quinone profiles for CLK-1 inhibitor in mouse macrophage cells;
  • B cells pre- incubated with CLK-1 inhibitors were treated with the fluorescence marker DCF, which produces green fluorescence when oxidized by cellular ROS. H2O2 is used to induce ROS in cells, and the reduction observed with CLK-1 inhibitors is shown as percentage relative to control; and
  • C COMET assay whereby fluorescent tails of DNA leaking from cell nuclei are used to measure DNA damage induced by ROS. Again H 2 O 2 was used to induce ROS, and data are expressed as percentage of cells with tails compared to control. The reduction of cells showing comets (% of total cells) in the presence of CLK-1 inhibitors is indicated.
  • Figure 10 Effects of Compounds 7 or 52 on serum creatinine levels in a rat model of ischemia-reperfusion.
  • Figure 11 Effects of Compounds 7 or 52 on Blood Urea Nitrogen (BUN) levels in a rat model of ischemia-reperfusion.
  • BUN Blood Urea Nitrogen
  • Figure 12 Effects of Compounds 7 or 52 on creatinine clearance in a rat model of ischemia-reperfusion.
  • Figure 13 Effects of Compounds 7 or 52 on urine protein concentration (g/L) in a rat model of ischemia reperfusion.
  • FIG 14 Effects of Compound 7 on lipoxygenase (LPO) levels in rats with lipopolysaccharide (LPS) induced lung injuriy.
  • LPO lipoxygenase
  • Figure 15 Effects of Compound 7 on protein contents in rats with LPS induced lung injury.
  • Figure 16 Effects of Compound 7 on total cells and neutrophils levels in rats with LPS induced lung injury.
  • Figure 17 Effects of Compound 7 on TNF- ⁇ levels in rats with LPS induced lung injury.
  • Figure 18 Effects of a treatment with Compound 138 in various dosages on soluble A ⁇ 1-40 determined by ELISA in hAPP751SL transgenic mice in the TBS fraction.
  • Figure 19 Effects of a treatment with Compound 138 in various dosages on soluble AB1-42 determined by ELISA in hAPP751SL transgenic mice in the TBS fraction.
  • Figure 20 Effects of a treatment with Compound 138 in various dosages on soluble A ⁇ i-40 determined by ELISA in hAPP751SL transgenic mice in the Triton X-100 fraction.
  • Figure 21 Effects of a treatment with Compound 138 in various dosages on soluble AB1-42 determined by ELISA in hAPP751SL transgenic mice in the Triton X- 100 fraction.
  • Figure 22 Effects of a treatment with Compound 138 in various dosages on bound AB1-40 determined by ELISA in hAPP751SL transgenic mice in the FA fraction.
  • Figure 23 Effects of a treatment with Compound 138 in various dosages on bound AB1-42 determined by ELISA in hAPP751SL transgenic mice in the FA fraction.
  • the present invention has yielded the unexpected discovery of a new class of compounds consisting of quinoline derivatives of formula A defined below which present CLK-1 inhibitory activity.
  • a pharmaceutically acceptable salt is meant to include any salt of the compounds of the invention that are suitable for use in contact with the tissues of human and lower animals without undue toxicity, irritation, or allergic response and are commensurate with a reasonable risk/benefit ratio.
  • Pharmaceutically acceptable salts are well known in the art (Pharmaceutical Salts Properties, Selection, and Use, Stahl, P. Heinrich / Wermuth, Camille G. (eds.), 2002. Monograph - ISBN 3-906390-26-8 - Verlag Helvetica Chimica Acta, Zurich).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately, by reacting a free basic function of the compounds of the present invention with a suitable acid or by reacting a free acidic function of the compounds of the invention with a suitable base such as, but not limited to, hydroxide, carbonate or bicarbonate of a pharmacologically acceptable metal cation.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfonate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphtalenesulfonate, oxalate, pramoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, nitrate, sulfate, bisulfate, phosphate, acid phosphate salts, glutamate, bicarbonate, p
  • the basic nitrogen-containing groups can be quaternized with such agents as alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides; and arylalkyl halides such as benzyl and phenylethyl bromides.
  • alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl, lauryl, myristyl, and
  • a pro-drug is a compound that, upon in vivo administration, is metabolized or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the parent compound, for example, by hydrolysis in blood. To produce a pro-drug, the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes.
  • the pro-drug may be designed to alter the metabolic stability or the transport characteristics of a drug (including improvement of bioavailability), to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • a pharmaceutically active compound By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, could design pro-drugs of the compound.
  • the present invention also contemplates metabolites formed by in vivo transformation of compounds having formula A or B.
  • the term metabolite refers to compounds formed by in vivo biotransformation of compounds having formula A or B by oxidation, reduction, hydrolysis, or conjugation.
  • alkyl refers to the saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, and cycloalkyl (alicyclic) groups.
  • aryl as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms (S, N, O), for example, unsubstituted or substituted benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • S, N, O heteroatoms
  • halogen designates F, Cl, Br or I.
  • optically active isomer designates any isomeric form of a claimed compound such as but not limited to an enantiomer, a diastereoisomer, a racemate or a mixture thereof.
  • pharmaceutically acceptable carrier it is meant a carrier medium which does not interfere with the effectiveness of the biological activity of the active ingredients of the composition, namely the compound of formula A, and which is not toxic to the host or patient. Furthermore, the carrier is advantageously a compound with minimum probability of being rejected by the immune system of the subject being treated. Suitable carriers are of common knowledge to one skilled in the art and will not be further detailed.
  • the term treatment refers to a process by which a disorder or its associated symptoms, for which inhibition of CLK-1 is beneficial, are alleviated or completely eliminated.
  • a disorder or its associated symptoms for which inhibition of CLK-1 is beneficial, are alleviated or completely eliminated.
  • one may understand that such treatment of the disorder or its associated symptoms may be alleviated or completely eliminated by, for instance, giving a compound of the present invention in appropriate formulation at appropriate doses to patients with high risk of/or early stages of disease.
  • prophylaxis refers to a process by which a disorder, or its associated symptoms, including but not limited to an age-related disorder, is obstructed, delayed or prevented.
  • a disorder for which inhibition of CLK-1 is beneficial refers to a disorder or its associated symptoms for which inhibition of CLK-1 is known or anticipated to be beneficial. More particularly, this expression refers to a disorder or its associated symptoms is alleviated or eliminated upon inhibition of CLK-1. Even more particularly, this expression refers to, but is not limited to, inflammation disorders, disorders caused by or exacerbated by oxidative stress and/or free radical-induced damage, including ROS mediated diseases, such as hypoxia / reoxygenation injury and ischemia / reperfusion injury. This expression also encompasses age-related disorders.
  • an age-related disorder refers to a disorder for which the incidence and/or prevalence increase with age, including, without being limited to, cardiovascular diseases, such as atherosclerosis, coronary artery disease and stroke; peripheral vascular disease; metabolic disorders such as Type Il diabetes, dyslipidemia, and hypertriglyceridemia; cancer, such as skin cancer, papillomas and age-dependent cancers; ischemia / reperfusion injury, such as renal, heart, cerebral ischemia and radiocontrast-induced nephropathy; inflammation; neurodegenerative disorders and dementia such as Alzheimer's disease, Parkinson's disease, Huntington's disease, memory disorders, and psychosis; Bladder and kidney disorders such as nephritis, nephropathy, end- stage renal disease (ESRD); Diabetes complications such as neuropathy, impaired wound healing, and retinopathy; eyes disorders such as age-related macular degeneration, dry-eye disease, glaucoma, retinitis pigmentosa, and cataracts; lung and respiratory vascular diseases, such as
  • inflammation is meant to intend a localized protective response elicited by injury or destruction of tissues which serves to destroy, dilute or wall off both the injurious agent and the injured tissue, characterized in the acute form by the classical sequence of pain, heat, redness, swelling, and loss of function, and histologically involving a complex series of events, including dilatation of the arterioles, capillaries, and venules with increased permeability and blood flow, exudation of fluids including plasma proteins, and leukocyte migration into the inflammatory focus. It is also characterized by massive release of TNF- ⁇ .
  • ischemia / reperfusion injury refers to the condition suffered by tissues and organs when deprived of blood flow, mostly due to the effects of inadequate nutrient and oxygen.
  • Reperfusion injury refers to the tissue damage inflicted when blood flow is restored after an ischemic period of generally more than about ten minutes. Ischemia and reperfusion can cause serious or fatal damage to afflicted tissues.
  • quinoline derivatives according to the present invention are the compounds having the following general formula (A), or their pharmaceutically acceptable salts or their pro-drugs:
  • R 2 when R 2 is hydrogen, then Ri is H or halogen, or R 1 is selected from the group consisting of: amino(3,4-dimethoxyphenyl)methyl, 2-hydroxyphenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 4-dimethylaminophenyl, pyridin-4-yl, 2- methoxypyridin-3-yl and 2-acetamidophenyl;
  • R 6 is selected from the group consiting of: Ci-C 6 alkyl, C 5 -C 6 aryl, benzyl, dimethylaminomethyl, phenylethyl and diphenylmethyl; and
  • ⁇ R 3 is selected from the group consisting of: H, methyl, phenyl, benzyl, 2-chlorophenyl, 2-methoxyphenyl, A- chlorophenyl, 4-methylphenyl, 4-isopropylphenyl, 3-hydroxyphenyl, A- hydroxyphenyl, 4-methoxyphenyl, 4-cyanophenyl, 4-dimethylamino-phenyl, 4-diethylamino-phenyl, 2,4-dichlorophenyl, 3,4-dimethoxyphenyl, A- methoxycarbonylphenyl, 3-methoxycarbonylphenyl, N-methylbenzamido, N-(3-methoxypropyl)benzamido, N,N-dimethylbenzamido, 4-(morpholin-4- ylcarbonyl)phenyl, 4-(pyridin-2-yl)phenyl, 4-(1 H-pyrazol-1-yl)phenyl, pyri
  • R 2 is selected from the group consisting of: pyridin-2-ylcarboxamido, pyridin-2-ylacetamido, 3- hydroxyphenylacetamido, 4-hydroxyphenylacetamido, ((2- methoxyphenyl)amino)methyl, ((3-methoxyphenyl)amino)methyl, ((3- methoxybenzyl)amino)methyl, 2-thienylacetamido and ((2- thienylmethyl)amino)methyl;
  • each of the compounds of formula (A) is not one of the compounds identified in Annex 1.
  • the compounds of Formula (A) of the invention comprising at least one asymmetric centre are either in the form of one of their enantiomers or a mixture thereof.
  • the compounds of formula (A) are the compounds wherein R 4 is
  • R 6 is selected from methyl, ethyl, n-propyl, /-propyl, n-butyl, /-butyl, ter-butyl, phenyl, benzyl, dimethylaminomethyl, phenylethyl, cyclohexyl, diphenylmethyl, pyridin-2-yl and pyridin-3-yl, the other substituents having the same meaning as previously defined.
  • the compounds of formula (A) are chosen in the group consisting of:
  • the pro-drugs of the compounds of formula (A) of the invention correspond to the compounds wherein the hydroxyl group in position 8 of the quinoline moiety is replaced by one of the following groups:
  • the above defined dihydrogen phosphate pro-drugs are in the form of their hydrochloride or dihydrochloride salts.
  • the preferred pro-drugs according to the invention are the following:
  • asymmetric or chiral centers may exist in the compounds of the present invention.
  • the present invention contemplates the various optically active isomers of the compounds of formula (A) and mixtures thereof.
  • an individual enantiomer of a compound of the present invention is prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of mixtures of enantiomeric compounds followed by resolution well-known to those of ordinary skill in the art.
  • the invention also relates to a method for inhibiting CLK-1 activity in a cell which comprises the following steps: a) providing a cell wherein CLK-1 activity needs to be inhibited, b) contacting the cell with a compound of formula (B):
  • Ri and R 2 are defined as follows: i) when R 2 is hydrogen, then Ri is H or halogen, or Ri is selected from the group consisting of: amino(3,4-dimethoxyphenyl)methyl, 2-hydroxyphenyl, 3- hydroxyphenyl, 4-hydroxyphenyl, 4-dimethylaminophenyl, pyridin-4-yl, 2- methoxypyridin-3-yl and 2-acetamidophenyl;
  • Ri is -CH(R 3 )NR 4 R 5 with
  • ⁇ R 4 H or CrC 4 alkyl
  • R 6 is selected from the group consiting of: Ci-C 6 alkyl, C 5 -C 6 aryl, benzyl, dimethylaminomethyl, phenylethyl and diphenylmethyl; and
  • ⁇ R 3 is selected from the group consisting of:
  • LJ or Ri is — c — N — R 7 and R 7 is -(CH 2 ) n -R8 where Rs is a C 5 -C 6 aryl optionally
  • R 2 is selected from the group consisting of: pyridin-2-ylcarboxamido, pyridin-2-ylacetamido, 3- hydroxyphenylacetamido, 4-hydroxyphenylacetamido, ((2- methoxyphenyl)amino)methyl, ((3-methoxyphenyl)amino)methyl, ((3- methoxybenzyl)amino)methyl, 2-thienylacetamido and ((2- thienylmethyl)amino)methyl; the compound of formula (B), when comprising at least one asymmetric centre, being in the form of one of its enantiomers or a mixture thereof; and c) determining the CLK-1 activity in the cell.
  • the compound of formula (B) used for inhibiting CLK-1 activity in a cell is selected from the group of compounds identified in Table 1.
  • 1 activity in a cell is selected from the group of:
  • the invention further relates to a method for the prophylaxis and/or treatment of a disorder or its associated symptoms for which inhibition of CLK-1 is beneficial, in animals, which comprises the following steps: a) identifying an animal having a disorder for which inhibition of CLK-1 is beneficial; and b) administering to the animal a compound of formula (B) as defined above, a pharmaceutically acceptable salt or a pro-drug thereof.
  • the compound of formula (B), its salt or its pro-drug or an optically active isomer, used for the prophylaxis and/or treatment in animal, of a disorder or its associated symptoms for which inhibition of CLK-1 is beneficial is selected from the group of compounds identified in Table 1.
  • the compound of formula (B), its salt or its pro-drug, used for the prophylaxis and/or treatment in animal, of a disorder or its associated symptoms for which inhibition of CLK-1 is beneficial is selected from the group of: ((7-((acetylamino)(3,4-dimethoxyphenyl)methyl)-5-chloroquinolin-8-yl)oxy)methyl dihydrogen phosphate 5,
  • the disorder for which inhibition of CLK-1 is beneficial is an ischemia / reperfusion injury, an inflammation or a neurodegenerative disorder or dementia.
  • the ischemia / reperfusion injury is a renal, heart, myocardium, lung, brain, or spinal cord ischemia / reperfusion injury.
  • the inflammation is a lung inflammation, a liver inflammation or an inflammation of any other organ and any clinical indications in which such inflammation is promoted.
  • a neurodegenerative disorder is Alzheimer's disease. Since it has been previously shown that inhibiting CLK-1 activity in mice slows down physiological aging (Liu et al., 2005), this indicates that the inhibition of CLK-1 activity in animals can delay the onset and severity of age-dependent diseases.
  • the present inventors have now disclosed that the compounds of formula (B) of the present invention are also effective to treat or prevent an age- related disorder or its associated symptoms.
  • the invention relates to a method for the prophylaxis and/or treatment of an age-related disorder or its associated symptoms, in animals, which comprises the following steps: a) identifying an animal having an age-related disorder; and b) administering to the animal a compound of formula (B), a pharmaceutically acceptable salt or a pro-drug thereof; with the proviso that said compound of formula (B) is not one of the following compounds, a pharmaceutically acceptable salt or a pro-drug thereof: 5-chloro-7-iodoquinolin-8-ol 52, 5-chloro-7-(2-hydroxyphenyl)quinolin-8-ol 56, or 5-chloro-7-(4-(dimethylamino)phenyl)quinolin-8-ol 60.
  • the above method is used for the prophylaxis and/or treatment of an age-related disorder or its associated symptoms selected from the group consisting of: cardiovascular diseases, such as atherosclerosis, coronary artery disease and stroke; peripheral vascular disease; metabolic disorders such as Type Il diabetes, dyslipidemia, and hypertriglyceridemia; cancer, such as skin cancer, papillomas and age-dependent cancers; ischemia / reperfusion injury, such as renal, heart, cerebral ischemia and radiocontrast-induced nephropathy; inflammation; neurodegenerative disorders and dementia such as Alzheimer's disease, Parkinson's disease, Huntington's disease, memory disorders, and psychosis; Bladder and kidney disorders such as nephritis, nephropathy, end-stage renal disease (ESRD); Diabetes complications such as neuropathy, impaired wound healing, and retinopathy; eyes disorders such as age-related macular degeneration, dry-eye disease, glaucoma, retinitis pigmentosa, and cataracts;
  • cardiovascular diseases such
  • the animal to be treated with the compound of formula (B) of the invention may be a human or any animal of commercial or domestic value including but not limited to cow, horse, pig, guinea pig, hamster goat, rabbit, chicken, dog, cat and birds. Even more preferably the animal treated is a human.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (A), a pharmaceutically acceptable salt or a pro-drug thereof as defined herein above, or any of the pro-drugs 5, 6, 136, 137, 138 and 139 defined above, formulated together with one or more non-toxic pharmaceutically acceptable carrier.
  • the present inventors have also shown that the compounds of formula (A) or (B) of the invention have a CLK-1 inhibitory activity.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula (A) or (B), a pharmaceutically acceptable salt or a pro-drug thereof, to effectively reduce and/or inhibit CLK-1 activity.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable amount of any one of the pro-drug 5, 6, 136, 137, 138 and 139 to effectively reduce and/or inhibit CLK-1 activity.
  • the compounds of the present invention could be combined with another drug known to be active to treat an age-related disorder or its associated symptoms, such as for example combination with a statin for the treatment of dyslipidemia.
  • compositions according to the invention may be specially formulated for oral administration in solid or liquid form, for parenteral injection, for rectal administration or topical administration.
  • the pharmaceutical compositions of this invention can be administrated to human and other animals orally, rectally, parenterally, intra cisternally, intravaginally, intraperitoneal ⁇ , topically (as by powder, cream, ointment, or drops), bucally, or as an oral or nasal spray.
  • These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like.
  • Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminium monostearate and gelatine.
  • the absorption of the drug in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug thus depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or fillers or extenders such as starches, lactose, sucrose, glucose, mannitol.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, propylene glycol, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, propylene glycol, glyce
  • the compounds of the invention may also be administered in the form of liposomes deriving from phospholipids or other lipid substances.
  • Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in aqueous medium. Any non-toxic, physiologically acceptable and metabolizable liquid capable of forming liposomes can be used.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines, both natural and synthetic.
  • Dosage forms for topical administration of a compound of the invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
  • the selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • Demethoxyubiquinone (DMQ) hydroxylation is carried by CLK-1 in eukaryotes and by UbiF in eubacteria.
  • CLK-1 inhibitor molecules were tested in a modified JF496 E. coli strain, which carries a mutation in the ubiF gene, and lacks DMQ hydroxylation activity. This strain is complemented either with mouse clk-1 gene, or with E. coli ubiF gene. This complementation is functional, and restores DMQ hydroxylation.
  • the rescued strains are capable of synthesizing ubiquinone (Q), instead of accumulating DMQ.
  • Test molecules are evaluated for specificity regarding Q synthesis inhibition, using the two modified strains.
  • Escherichia coli strain JF496 (ubiF-) was transformed with plasmids containing the mouse clk-1 gene, or the E. coli ubiF gene. For general growth, a clone of each strain is grown overnight at 37°C in 5 ml LB supplemented with ampicillin
  • M9-LB 0.5/0.5:v/v
  • M9 medium supplemented with (1 mM MgSO 4 , 20 ⁇ M CaCI 2 , 0.5 ⁇ g/mL thiamine, 0.12% casamino acids, 40 ⁇ g/mL D-L-methionine, 100 ⁇ g/mL L-asparagine, trace metals, 0,5% glucose), and of LB medium.
  • Media contain ampicillin (50 ⁇ g/mL) for plasmid selection.
  • the JF496-ubiF and JF496- mclk-1 strains are diluted from an overnight preculture into M9-LB (0.5/0.5:v/v) to an OD 6O o of 0.03.
  • a volume of 750 ⁇ l of bacteria is transferred to 15 ml tubes.
  • the bacterial cultures are incubated for 5 hours at 37 0 C with agitation.
  • DMQ Demethoxyubiquinone
  • Q ubiquinone
  • CLK-1 is a demethoxyquinone (DMQ) hydroxylase that catalyzes the penultimate step in Q biosynthesis. Inhibition of CLK-1 leads to accumulation of the reaction precursor, DMQ. This assay measures the endogenous cellular levels of Q, and its precursor DMQ. In all cells tested the levels of DMQ present normally are negligible, so robust inhibition of CLK-1 leads to a profound change in the HPLC quinone profiles of treated cells.
  • DMQ demethoxyquinone
  • Fresh dilutions of compounds that are identified from the bacterial screen were dissolved overnight in dimethyl sulfoxide (DMSO) at a concentration of 10 mM. Dilutions of the compound (in DMSO) were added to wells of RAW264.7 cells, an Abelson's murine leukemia virus-transformed murine macrophage cell line. The cells were plated (1 x 10 5 cells per well) in Dulbecco's Modified Eagle's medium (supplemented with 10% Fetal Bovine serum, 1% Penicillin/Streptomycin, 100 ⁇ M Sodium Pyruvate) the day before compound treatment and left in a humidified CO 2 incubator (5% CO 2 , 37 0 C) overnight. Following addition of the compound, the plates were incubated for 24 hours, in humidified CO 2 (5% CO 2 , 37 0 C).
  • DMSO dimethyl sulfoxide
  • Table 1 shows a list of compounds which have been determined to be active CLK-1 inhibitors.
  • Shown in Figure 3 is a typical HPLC profile obtained from quinone extraction of a sample of RAW 264.7 mouse macrophage cells.
  • the graph in the upper panel represents the quinone extracted from untreated macrophages, wherein the major species evident is ubiquinone-9, or Q.
  • ubiquinone-9 or Q.
  • DMQ quinine peak
  • This profile represents cells treated with compound 135.
  • CLK-1 inhibitors are readily identified by a clear and simple visual analysis of HPLC profiles of cells treated with putative candidate inhibitors. A variety of human and mouse cell lines were examined, with no major difference between them other than variations in levels of endogenous ubiquinone.
  • CLK-1 activity may have impacts on cellular ROS levels by regulating the cellular content of Q, which contributes to ROS production via the electron transport chain and ROS scavenging. Therefore, it is to be expected that inhibition of CLK- 1 will lead to alterations in cellular ROS levels. Additionally, one of the macromolecules that is targeted by ROS in cells is DNA, resulting in DNA damage. One might expect that DNA damage would also be reduced as a consequence of CLK-1 inhibition. We therefore used two assays to measure these factors in living cells, as outlined below.
  • DCF-DA (2,7-dichlorofluorescein diacetate) was used to assess cellular ROS levels.
  • the lipophilic DCF-DA is transported across the cell membrane to the cytosol, and enzymatically converted to hydrophilic 2,7-dichlorofluorescein (DCFH) by cytosolic esterase(s).
  • DCFH hydrophilic 2,7-dichlorofluorescein
  • Cellular ROS oxidize DCFH to DCF, which is a fluorescent molecule.
  • mouse macrophage cells (RAW264.7) seeded (1 x 10 5 per well) in 96-well plates were treated with CLK-1 inhibitors for 24h.
  • the cells were then incubated with 20 ⁇ M DCF-DA in Hanks' Balanced Salt Solution (HBSS) for 30 min at 37°C.
  • HBSS Hanks' Balanced Salt Solution
  • the fluorescence from cellular DCF was then monitored using a fluorescence plate reader (excitation 488 nm and emission 520 nm).
  • the protein amount in the tested wells was determined using a commercially available BCA protein assay kit. Cellular ROS levels were subsequently expressed as mean DCF fluorescence/mg protein from 3 replicates.
  • RAW264.7 cells were seeded (2.5 x 10 6 cells per well) in the presence/absence of a CLK-1 inhibitory compound in 12-well plates. After 24 hours, the cells were treated with 1 mM H 2 O 2 for 1 hour, to induce ROS-mediated DNA damage. The cells were then washed twice in ice-cold PBS, before being scraped into 575 ⁇ l of ice cold PBS. 75 ⁇ l of this mixture was removed and added to 750 ⁇ l ice cold PBS. A 10 ⁇ l aliquot was removed and mixed with 90 ⁇ l of molten low-melting point agarose. 75 ⁇ l of this cell-agarose mix was pipetted onto a glass slide, which was placed flat at 4 0 C, and shielded from the light for 15 minutes.
  • the slide was immersed in a pre-chilled lytic solution and left for 1 hour, at 4 0 C, shielded from the light. Subsequently, the slide was removed and after removal of excess lytic solution, immersed in a freshly prepared alkaline solution (pH 13). The slide was then left for 1 hour, shielded from the light, at room temperature.
  • Renal function Creatinine clearance On day 0, creatinine clearance in each group was not statistically different. On days 3 and 7 creatinine clearance in group treated with compound 7 or compound 52 was significantly higher than in group NA ⁇ VE. On days 11 and 14 creatinine clearance in group treated with compounds 7 or 52 was not statistically different compared with group NA ⁇ VE, however was higher than in group NA ⁇ VE on day 14 ( Figure 12).
  • 24-hr urine protein in each group was not statistically different.
  • 24-hr urine protein in group treated with compounds 7 or 52 was significantly lower than in group NA ⁇ VE.
  • 24-hr urine protein in group treated with compound 7 or 52 was not statistically different compared with group NA ⁇ VE.
  • the renal function data serum creatinine, blood urea nitrogen (BUN), creatinine clearance and urine protein
  • BUN blood urea nitrogen
  • creatinine clearance and urine protein showed that once a day intraperitoneal treatment with compound 7 (2.5 mg/kg) and compound 52 (20 mg/kg) starting three days before the ischemic event and continued for 11 consecutive days effectively prevented, in a similar extent, the renal ischemia/reperfusion injury in one kidney rat model after 60-min ischemia when compared with the Na ⁇ ve control groups.
  • renal functions in the SHAM groups were not affected.
  • the protective effect on several parameters of the renal function was particularly pronounced on days 3 and 7 after the ischemia/reperfusion.
  • LPS lipopolysaccharide
  • Drug-treated rats received intraperitoneal ⁇ (i.p.) Compound 7 or N-Acetyl-L-cysteine (NAC) as reference.
  • Compound 7 was administered i.p. in vehicle containing DMA/PG/Tween 80 and water. Doses were given once a day, for three consecutive days, with the last dose administered 1 h before LPS exposure. Control rats received drug vehicles as indicated. Freshly prepared drugs were administered in a volume of 5 or 10 ml/kg or 5 ml/kg. Twenty-four hours after i.p.
  • LPS or saline administration the animals were sacrificed by an overdose of urethane and blood alveolar fluid (BALF) was collected for total and differential cell counts, LPO and TNF- ⁇ determination and protein contents.
  • BALF blood alveolar fluid
  • Compound 7 effectively reduced the increase in LPO in BALF to levels comparable to those observed in NAC-treated rats.
  • Compound 7 failed to reduce the increase in BALF protein.
  • Compound 7 (10 mg/kg) was effective to significantly reduce BALF TNF- ⁇ levels.
  • histological analysis demonstrated that Compound 7 at 5 mg/kg, Lp. was effective to reduce the intensity of the interstitial pattern (alveolar wall is less thick in treated lungs) and the inflammatory response (lower number of inflammatory cells).
  • CLK-1 inhibitors are protective, the utility of the novel derivatives of quinoline for clinical indications in which such inflammation is promoted represents a particularly useful embodiment.
  • Example 6 Assessment of the effects of a treatment with Compound 138 on brain ⁇ -amyloid1-40 and ⁇ -amyloid1-42 levels of hAPP751SL transgenic mice.
  • Animal Male hAPPSL transgenic (tg) mice (C57BL/6 background) aged 5 months ( ⁇ 2 weeks) at the starting date of the study.
  • Transgenic hAPP751SL animals constitutively over-express human APP751 with the London (V717I) and the Swedish (K670M/N671 L) mutations under the regulatory control of the neuronal tissue specific murine-Thy-1 promoter. Due to the London mutation, high levels of ⁇ -amyloid1-42 are expressed all over the brain but mainly in cortex and hippocampus.
  • High levels of ⁇ -amyloid1-42 are associated with amyloid plaque formation in the CNS at a much earlier age beginning at 3 months.
  • Enhanced brain A ⁇ i-42 levels as seen in this mouse model are associated with earlier plaque formation.
  • a ⁇ i-42 accelerates amyloid deposition and promotes formation of denser deposits; while A ⁇ i-40 might have opposite effects. Therefore, the potential to influence the generation of this fatal amyloid peptide might be advantageous, in particular with regard to a possible treatment of Alzheimer's disease patients.
  • Treatment Compound 138 was formulated in carboxymethyl cellulose (CMC) and administrated per os (p.o.) to animals once daily and twice daily (at the highest dose), respectively, for 60 consecutive days. Treatment doses were 5, 20, 50 and 2 x 50 mg/kg b.w./day, respectively or with vehicle (CMC).
  • CMC carboxymethyl cellulose
  • mice were transcardially perfused with physiological (0.9%) saline until the whole blood was washed out; then brains were rapidly removed and the right hemisphere was immersion fixed in fresh 4% paraformaldehyde for one hour. After that the hemispheres were transferred to a 15% sucrose solution for cryprotection. On the next day, brains were frozen on dry ice and stored at -8O 0 C. The left brain hemisphere was immediately snap frozen on dry ice to determine ⁇ -amyloid1-40 and ⁇ -amyloid1-42 in four brain homogenate fractions.
  • a ⁇ 1-40 and A ⁇ i-42 were used for evaluation of brain A ⁇ 1-40 and A ⁇ i-42 in four (4) brain fractions which are TBS, Triton X-100 and FA.
  • a ⁇ 1-40 and AB1-42 was using high sensitivity ELISA kits (TK40HSTM; TK42HSTM) manufactured by The GENETICS Company, Switzerland.
  • TBS extract fractions contain the water soluble AB1-40 and AB1-42 fraction of the brain tissue while in the Triton x-100 fraction smaller polymers like protofibrils are solubilized.
  • the formic acid (FA) fractions contain the insoluble polymerised A ⁇ . Results are shown in Figures 18 to 23.
  • Compound 138 significantly reduces A ⁇ 1- 42 levels in the TBS (5 and 20mg/kg; Fig.19) and in the Triton x-100 fraction (5, 20 and 50mg/k; Fig.21).
  • TBS fractions Fig. 18 and 19
  • Triton fractions Fig. 20 and 21
  • a similar but, however, not significant effect can be seen in terms of A ⁇ 1-40 where all individual data points are very close together in the two Compound 138 groups.
  • Compound 138 has a significant effect on APP processing and on generation of A ⁇ peptide, though the effects were more pronounced on A ⁇ 1-42.
  • Clear AB1 -42 lowering effects can be seen across various brain fractions, which represent different polymerization states of ⁇ -amyloid (monomers, oligomers, fibrils).
  • intima rte mixture of 5-chloro-8-hydroxyquinoline (1.5g, 8.7mmol), 3,4- dimethoxybenzaldehyde (2.85g, 17.4mmol) and acetamide (1.03g, 17.4mmol) was sealed in a microwave reactor vessel.
  • the vessel was placed in a microwave reactor (Biotage Initiator) and heated to 18O 0 C for 1 hour.
  • the cooled reaction mixture was triturated with ethyl acetate and the resulting solid filtered off. This solid was further triturated with ethanol to yield the title compound as a white solid (2.2g, 65%).
  • Example 7_2_ N-((5-chloro-8-hydroxyquinolin-7-yl)(quinolin-3- yl)methyl)acetamide (Compound 19) ⁇ Method A_1 ⁇
  • Methyl iodide (147mg, 1.03mmol) and 1-(8-(benzyloxy)-5-chloroquinolin-7-yl)-N- (diphenylmethylene)methanamine (480mg, 1.03mmol) were dissolved in anhydrous tetrahydrofuran (0.5ml) and cooled to O 0 C. To this mixture was added dropwise a solution of potassium fe/f-butoxide (128mg, 1.16mmol) in tetrahydrofuran (0.13ml). The mixture was allowed to warm to RT and after 1 hour the reaction was concentrated. The residue was dissolved in ethyl acetate and washed with water and brine.
  • Dibenzyl phosphate (2.64 g, 9.48 mmol), sodium bicarbonate (3.18 ml_, 11.97 mmol) and tetra-n-butylammonium hydrogen sulfate (3.2 g, 9.48 mmol) were dissolved in water (80 ml).
  • Dichloromethane (DCM, 90 ml_) was added and the mixture was vigorously stirred at O °C for 10 min, followed by the addition of chloromethyl chlorosulfate (1.17 ml_, 11.37 mmol) in DCM (15 ml_) with continuous vigorous stirring overnight at room temperature. The organic layer was separated, washed with brine, dried (MgSO 4 ) and evaporated.
  • Miyadera H., Amino, H., Hiraishi, A., Taka, H., Murayama, K., Miyoshi, H., Sakamoto, K., Ishii, N., Hekimi, S. and Kita, K., Altered quinone biosynthesis in the long-lived clk-1 mutants of Caenorhabditis elegans, J Biol Chem, 276(11), 7713, 2001.

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