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WO2003013420A2 - Derives d'isoprenyl et leur utilisation pour traiter et prevenir l'osteoporose et la calcification cardio-vasculaire - Google Patents

Derives d'isoprenyl et leur utilisation pour traiter et prevenir l'osteoporose et la calcification cardio-vasculaire Download PDF

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WO2003013420A2
WO2003013420A2 PCT/EP2002/008917 EP0208917W WO03013420A2 WO 2003013420 A2 WO2003013420 A2 WO 2003013420A2 EP 0208917 W EP0208917 W EP 0208917W WO 03013420 A2 WO03013420 A2 WO 03013420A2
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group
compound
pharmaceutically acceptable
treatment
calcification
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PCT/EP2002/008917
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English (en)
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WO2003013420A3 (fr
Inventor
Ceer Vermeer
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Vitak Bv
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Priority to AU2002333378A priority Critical patent/AU2002333378A1/en
Priority to EP02794586A priority patent/EP1414387A2/fr
Publication of WO2003013420A2 publication Critical patent/WO2003013420A2/fr
Publication of WO2003013420A3 publication Critical patent/WO2003013420A3/fr
Priority to US10/770,991 priority patent/US20050176778A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/02—Quinones with monocyclic quinoid structure
    • C07C50/06—Quinones with monocyclic quinoid structure with unsaturation outside the quinoid structure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/10—Quinones the quinoid structure being part of a condensed ring system containing two rings
    • C07C50/14—Quinones the quinoid structure being part of a condensed ring system containing two rings with unsaturation outside the ring system, e.g. vitamin K1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
    • C07C69/616—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters

Definitions

  • Isoprenyl derivatives and their use in the treatment and prevention of osteoporosis and cardiovascular calcification
  • the present invention is in the field of organic chemistry, biochemistry, and medicine. More in particular, the invention relates to isoprenyl derivatives and their use to prevent postmenopausal and juvenile or senile loss of bone mass, as well as to prevent calcification of the arteries and heart valves.
  • Vitamin K is a group name for a number of structurally related compounds which have in common a methylated naphthoquinone group, but which differ in the aliphatic side chain at the 3-position. This may be phytyl (vitamin K-1), geranylgeranyl (menaquinone-4, menatetrenone), or polyisoprenyl (vitamin K-2, menaquinone-n).
  • vitamin K-1 geranylgeranyl
  • Menaquinone-4 menatetrenone
  • polyisoprenyl vitamin K-2, menaquinone-n.
  • the classical function of vitamin K is that it serves as a co-factor for ⁇ -glutamyl carboxylase, an endoplasmic enzyme which catalyzes the posttranslational carboxylation of glutamate residues into ⁇ -carboxy glutamate (Gla).
  • Gla-residues are calcium binding groups in proteins which are required for the biological activity of the proteins in which they occur.
  • the active co-factor for ⁇ -glutamyl carboxylase is vitamin K hydroquinone, which is generated by the action of either of two reductases: a dithiol-dependent enzyme which can be completely blocked by coumarin derivatives, and a NADPH-dependent enzyme which is insensitive to coumarins but requires higher intakes of vitamin K.
  • a dithiol-dependent enzyme which can be completely blocked by coumarin derivatives
  • NADPH-dependent enzyme which is insensitive to coumarins but requires higher intakes of vitamin K.
  • the Gla- residues are not formed, so that the respective proteins are synthesized in an under- carboxylated, i.e. inactive form.
  • Gla-containing proteins The two major groups of Gla-containing proteins are: (i) certain blood coagulation factors which are synthesized in the liver, and (ii) osteocalcin and Matrix Gla- Protein ("MGP"), two proteins involved in the regulation of tissue calcification which are produced in bone (osteocalcin), cartilage (MGP), and vascular smooth muscle cells (also MGP).
  • MGP Matrix Gla- Protein
  • the first clinical sign of systemic administration of coumarin derivatives is the (hepatic) synthesis of inactive blood coagulation factors.
  • a regimen was developed in which animals received a mixture of the coumarin derivative warfarin and vitamin K-1. The latter can be reduced to the active cofactor for ⁇ -glutamyl carboxylase by the NADPH- dependent reductase which is present in the liver but could not be demonstrated in bone and vascular tissue.
  • Bisphosphonates are structural analogs of pyrophosphate which competitively inhibit the formation of famesyl pyrophosphate (famesyi PP) and geranylgeranyl pyrophosphate (geranylgeranyl PP) in the mevalonate pathway.
  • the resulting farnesyl PP and geranylgeranyl PP are required for prenylation and targeting of essential proteins in signal transduction (e.g. Ras, Rho, Rac).
  • Geranylgeranyl PP is especially used in the activation of osteoclasts, the cells involved in bone resorption [Van Beek E., et al., J. Bone Miner. Res. 14 (1999) 722-729]. Inhibition of prenylation leads to disturbance of signal transduction and apoptosis of osteoclasts, so that postmenopausal bone loss is retarded, and even increase of bone mass is possible.
  • bisphosphonates are a powerful tool for preventing osteoporosis and related fractures.
  • a drawback is the often reported side-effect of gastrointestinal complaints.
  • Vascular calcification may occur as a result of atherosclerosis, but also as a result of diabetes mellitus (Monckeberg's sclerosis) and renal failure. It is the result of two processes: precipitation of calcium salts (often seen in an early stage), and formation of vascular bone tissue. The latter phase is characterized by the presence of osteoblast- and osteoclast-like cells, and a variety of proteins known to occur in bone where they have a function in the control of bone growth and development [Shanahan, CM., et al., J. Clin. Invest.
  • MK-4 menaquinone-4
  • MK-4 may be regarded as a geranylgeranyl derivative in which the pyrophosphorylation is effectively prevented by the presence of the naphthoquinone group.
  • MK-4 will act as an inhibitor of the mevalonate pathway, with a function complementary to that of bisphosphonates.
  • non-toxic biologically active compound having the following general formula (I):
  • R is an organic moiety, selected from the group consisting of a naphthoquinone or benzoquinone derivative (both optionally substituted); a group P-C(R1)-P, where each P stands for a -PO(OH) 2 group and R., is a (poly)isoprenyl group, hydroxy, halogen (preferably chloro or bromo), or hydrogen; an ester group R m C(O)O, e.g.
  • R m , R p an R q each independently stand for a C- ⁇ o alkyl (branched or straight), a C 3 .
  • cycloalkyl a three to ten- membered heterocyclic (having one or more N, O and/or S atoms as hetero atoms), a C 3- 20 cycloalkyl C 1-10 alkyl, a three to ten-membered heterocyclic C 1-10 alkyl (having one or more N, O and/or S atoms as hetero atoms), and an aryl or aryl C 1-10 alkyl, where aryl stands for an aromatic or heteroaromatic (having one or more N, O and/or S atoms as hetero atoms), monocyclic or polycyclic ring system (the latter having preferably two, three or four rings), where all of these groups may be optionally substituted by one or more heteroatoms, such as N, O and/or S, and n is an integer from 1 to 14, preferably from 2 to 4, or a pharmaceutically acceptable derivative thereof.
  • the compounds of formula (I) as defined above are believed to be new, in particular when used as active ingredients in
  • a compound as defined above, or a pharmaceutically acceptable salt thereof is provided in the preparation of a medicament for the treatment or prevention of certain disorders in a mammal, especially a human being.
  • disorders are selected from the group consisting of postmenopausal loss of bone in women, juvenile or senile osteoporosis in men and women, cardiovascular calcification, including arteriosclerotic and atherosclerotic calcification of the vascular intima, M ⁇ nckeberg's sclerosis of the tunica media, and calcification of arterial valves, other ectopic calcifications, such as in pancreatic calcification, renopathy, or malignancies including primary and secondary bone tumors and metastases.
  • pharmacologically active substances selected from the group consisting of bisphosphonates, estrogens, calcitonins, and low doses of vitamins D and/or K.
  • an N-containing bisphosphonate e.g., pamdronate, alendronate, olpadronate, thandronate, risedronate, zoledronate, and the like
  • an N-containing bisphosphonate e.g., pamdronate, alendronate, olpadronate, thandronate, risedronate, zoledronate, and the like
  • a pharmaceutical composition comprising, as an active ingredient, a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, in conjunction with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises one or more pharmacologically active substances selected from the group consisting of bisphosphonates, estrogens, calcitonins, and low doses of vitamins D and/or K, in particular a bisphosphonate compound.
  • a method of treatment for treating or preventing certain disorders in a mammal, especially a human being, which comprises administering to said mammal an effective amount of a compound of formula (I), preferably in conjunction with a pharmaceutically acceptable carrier.
  • the present invention is based on the discovery that prenylation of proteins is necessary for signal transduction, and that bisphosphonates inhibit the formation of farnesyl PP and geranylgeranyl PP which is an essential step in protein prenylation.
  • Prenylation is meant to indicate an addition or substitution reaction by a functionalized isoprenyl or polyisoprenyl moiety.
  • polyisoprenyl usually two to four isoprenyl units are present.
  • Bisphosphonates probably act as structural analogs of the pyrophosphate to be coupled to the polyisoprenyl chains.
  • geranylgeranyl PP is involved in the activation of osteoclasts, resulting in increased bone turnover, and rapid loss of bone mass.
  • vascular calcification is regulated by the same cells and the same proteins as those found in bone, but that there is an inverse association between osteoporotic bone loss and vascular calcification.
  • MK-4 has the structure of vitamin K-1 in which the phytyl side-chain is replaced by geranylgeranyl (4 isoprenyl residues).
  • MK-4 is the only K-vitamin with a geranylgeranyl side chain, and several studies have demonstrated that the action of high doses of MK-4 (45 mg/day, i.e. 500- 1 ,000x the RDA for vitamin K) on bone is comparable with that of bisphosphonates. Although experimental proof for its mode of action is lacking, the very high dose required and the fact that similar effects were not obtained for vitamin K-1 [Hara, K., et al., Bone 6 (1995) 179-184] make it unlikely that the effects of MK-4 on bone are solely due to its classical vitamin K function.
  • the compounds according to this invention with formula l as defined above show interesting pharmacological properties, in particular in preventing cardiovascular calcification, which make them potentially useful in medicine to treat or prevent certain disorders, especially in humans.
  • the present invention relates in one aspect to compounds lacking vitamin K activity which have retained the potential of interfering with the mevalonate pathway and thus inhibit osteoclast activation.
  • the methylated naphthoquinone group of MK-4 is replaced by a group without vitamin K activity.
  • groups R include structurally related groups such as (non-methylated) naphthoquinone and benzoquinone, both optionally substituted.
  • Another preferred group of compounds of formula (I) are new bisphosphonate derivatives having the basic structure P-C(R 1 ,R 2 )-P, where each P stands for a -PO(OH) 2 group and at least one of R., and R 2 is a (poly)isoprenyl group as defined in formula (I), and the other one of R-, and R 2 preferably is the same or a different (poly)isoprenyl group or hydroxy, a halogen (preferably, chloro or bromo), or hydrogen.
  • P stands for a -PO(OH) 2 group and at least one of R.
  • R 2 is a (poly)isoprenyl group as defined in formula (I)
  • the other one of R-, and R 2 preferably is the same or a different (poly)isoprenyl group or hydroxy, a halogen (preferably, chloro or bromo), or hydrogen.
  • Preferred compounds which are expected to be active as competitive inhibitors of geranylgeranyl PP formation are those containing the polyisoprenoid backbone of either geranyl or farnesyl or geranylgeranyl, which are shown in the following structural formulas:
  • active inhibitors according to the present invention preferably have, in formula (I), a group R at the comparable OH-position, which is either directly coupled to the first carbon atom of the polyisoprenyl moiety or which includes, for instance, an ether or ester linkage.
  • preferred compounds according to the present invention are for example geranyl, farnesyl, and geranylgeranyl derivatives with a similar structure, such as non-methylated 3-geranylgeranyl naphthoquinone, geranylgeranyl benzoquinone, and trityl-geranylgeraniol.
  • the compounds of formula (I) as defined above can be prepared in various ways.
  • the methods as such are known in the art for the preparation of structurally related or similar compounds, for example vitamin K2.
  • Some of these methods have been reviewed in EP-A-0243849, the disclosure of which is incorporated herein by reference.
  • a polyprenyl alcohol compound such as geranyl alcohol or farnesyl alcohol which are commercially available, is coupled to a compound of the formula RH or a functionalized derivative thereof, preferably in the presence of a suitable catalyst, e.g. a an acid Friedel-Crafts catalyst.
  • a suitable catalyst e.g. a an acid Friedel-Crafts catalyst.
  • Appropriate measures should be taken to protect double bonds or other groups which may interfere with the coupling reaction.
  • Compounds of formula (I) which have an ester function can also be prepared by esterification where the (poly)isoprenyl moiety is usually provided as a (commercially available) alcohol, and the "R" part which sometimes is a mimic of 2-methylnaphtoquinone is usually provided as an acid, such as a derivative of benzoic acid, 1-naphthylacetic acid, quinaldic acid, chelidamic acid, and the like.
  • the compounds of formula (I) can be present, with reference to the (first) double-bond, viewed from the R group, in the isoprenyl chain, in Z form (also called cis- form) or in E-form (also called trans form) or as a mixture of these two forms.
  • Z form also called cis- form
  • E-form also called trans form
  • Z-form is biologically less active, if not even inactive, and therefore the E-form generally is preferred.
  • the compounds of formula (I) may comprise one or more asymmetric carbon atoms, giving rise to enantiomeric forms, or mixture(s) thereof. It should be understood that all such enantiomeric and/or E- or Z-forms, whether in a substantially single form or a mixture, in purified or non-purified form, are encompassed by the present invention.
  • a pharmaceutical composition comprising a compound of formula I and/or one or more pharmaceutically acceptable derivatives thereof as an active ingredient is suitably administered to humans by way of oral or parenteral administration.
  • Pharmaceutically acceptable derivatives are meant to include any form of the active substance of formula (I) as defined above, which is suitable for administration to a mammal, in particular a human.
  • Such pharmaceutically acceptable derivatives include the usual acid addition salts, but also ester and amide forms, and the like, where appropriate.
  • a compound of formula (I) or a pharmaceutically acceptable derivative thereof may also comprise solvates of such compounds, such as, e.g., a hydrate. All such forms are known to a person skilled in the art, who can also make an appropriate selection without inventive skill.
  • the medicament can be administered in conventional form for oral administration, e.g. as tablets, lozenges, dragees and capsules. However, for the administration of the drug to children, should the occasion arise, it may be preferred to formulate the composition as an oral liquid preparation such as a syrup, a nasal spray, or a suppository.
  • the medicament can also be administered parenterally, e.g. by intramuscular or subcutaneous injection, using formulations in which the medicament is employed in a saline or other pharmaceutically acceptable, injectable composition.
  • An amount effective to treat the disorder hereinbefore described depends on the usual factors such as the nature and severity of the disorder being treated, the weight of the patient, the specific compound(s) of choice, and considerations and preferences of the prescriber.
  • the amount of active ingredient(s) to be administered usually will be in the range of micrograms up to 100 mg or more per dose.
  • a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active ingredient.
  • Unit doses will normally be administered once or more than once per day, for example 1 , 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult, of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kg/day.
  • the compound of formula I and/or pharmaceutically acceptable derivative(s) thereof according to the invention is administered in the form of a unit-dose composition, such as a unit dose oral, sub-lingual, rectal, topical or parenteral (especially intravenous) composition.
  • a unit-dose composition such as a unit dose oral, sub-lingual, rectal, topical or parenteral (especially intravenous) composition.
  • compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories.
  • Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
  • the preparation of such compositions is well known to people skilled in the art and can be optimized in a routine way without exerting inventive skill and without undue experimentation.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monoole
  • Oral formulations further include controlled release formulations which may also be useful in the practice of this invention.
  • the controlled release formulation may be designed to give an initial high dose of the active material and then a steady dose over an extended period of time, or a slow build up to the desired dose rate, or variations of these procedures.
  • Controlled release formulations also include conventional sustained release formulations, for example tablets or granules having an enteric coating.
  • Nasal spray compositions are also a useful way of administering the pharmaceutical preparations of this invention to patients such as children for whom compliance is difficult.
  • Such formulations are generally aqueous and are packaged in a nasal spray applicator which delivers a fine spray of the composition to the nasal passages.
  • Suppositories are also a traditionally good way of administering drugs to children and can be used for the purposes of this invention.
  • Typical bases for formulating suppositories include water-soluble diluents such as polyalkylene glycols and fats, e.g. cocoa oil and polyglycol ester or mixtures of such materials.
  • fluid unit dose forms are prepared containing the compound and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised usually by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
  • the "Vitamin K1 plus warfarin” model was used to test effects of isoprenyl derivatives on vascular calcification.
  • This model is also referred to as the "KW model for calcification” or "KW model”. Because of the parallels between vascular calcification and calcium metabolism in bone, the model is regarded to be valid for describing potential effects on bone. Whereas in this model the bone deformations will not become visible before 9 months of treatment, calcification of the large arteries is usually apparent within 4 weeks of treatment.
  • This model therefore provides an excellent in vivo model to test the compounds according to the invention for their tissue distribution, toxicity and effectivity. The effectiveness of this approach was demonstrated by using relatively small amounts of MK-4 in combination with an excess of vitamin K-1.
  • MK-4 since MK-4 possesses vitamin K activity, it will be involved in the production of Gla-proteins, some of which may act as calcification inhibitors.
  • the observed effects under the conditions chosen suggest, however, that MK-4 has a second activity which is not related to its naphthoquinone group, but which is completely different from the classical function of vitamin K. (The present invention is inter alia based on the discovery of this second activity).
  • the treatment of subjects and patients with MK-4 in order to prevent or to cure osteoporosis and/or vascular calcification seems to be indicated.
  • a drawback of such treatment is that patients at risk for thrombosis often receive vitamin K-antagonists to counteract severe cardiovascular events such as myocardial infarction and stroke. Treatment of such patients with MK-4 or any other substance showing vitamin K activity may therefore result in a high mortality in this patient group.
  • the present invention relates to compounds and compositions lacking vitamin K activity which have retained the potential of interfering with the mevalonate pathway and thus inhibit osteoclast activation.
  • experiment 1 the dietary requirement of vitamin K-1 was measured in untreated male Lewis rats, 6 weeks of age, on the basis of blood coagulation tests after a treatment period of 4 weeks. At an intake of 40 microgram vitamin K-1 per kg body weight per day, the synthesis of coagulation factors had reached its (maximal) plateau level.
  • the daily food intake was recorded, and the body weight of the animals was measured regularly. After four weeks of treatment at the indicated doses again blood was taken and prothrombin concentrations were measured. Mean prothrombin concentrations in the groups were: 23%, 48%, 82%, 98%, 102%, and 99% of pooled normal rat reference plasma. Based on these data it was decided that the diet containing 0.6 mg of vitamin K-1 per kg supplied sufficient vitamin K to maintain normal prothrombin synthesis. This amount corresponds with an intake of 40 micrograms of vitamin K-1 per kg body weight per day.

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Abstract

L'invention concerne un composé non toxique biologiquement actif représenté par la formule (I) ou un dérivé de celui-ci pharmaceutiquement acceptable. Dans cette formule, n est un nombre entier compris entre 1 et 14 et, de préférence, entre 2 et 4; R représente une fraction organique, de préférence, un groupe différent de 2-methyl naphthoquinone mais de structure sensiblement similaire, ou un groupe P-C(R1)-P, où chaque P représente un groupe -PO(OH)2; et R1 représente un groupe (poly)isoprényl, hydroxy, halogène (de préférence, chloro ou bromo) ou hydrogène. On utilise ces composés pour traiter ou prévenir certains troubles des mammifères, notamment des humains, par exemple, en cas de perte osseuse postménopausale chez la femme, d'ostéoporose juvénile ou sénile chez les hommes et les femmes, de calcification cardio-vasculaire et d'autres calcifications ectopiques.
PCT/EP2002/008917 2001-08-03 2002-08-05 Derives d'isoprenyl et leur utilisation pour traiter et prevenir l'osteoporose et la calcification cardio-vasculaire WO2003013420A2 (fr)

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AU2002333378A AU2002333378A1 (en) 2001-08-03 2002-08-05 Isoprenyl derivatives and their use in the treatment and prevention of osteoporosis and cardiovascular calcification
EP02794586A EP1414387A2 (fr) 2001-08-03 2002-08-05 Derives d'isoprenyl et leur utilisation pour traiter et prevenir l'osteoporose et la calcification cardio-vasculaire
US10/770,991 US20050176778A1 (en) 2001-08-03 2004-02-02 Isoprenyl derivatives and their use in the title treatment and prevention of osteoporosis and cardiovascular calcification

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EP01202955 2001-08-03

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004019923A1 (fr) * 2002-08-30 2004-03-11 Vitak Bv Compositions contenant de la vitamine k pour le traitement ou la prevention du raidissement des arteres du a l'age
GB2476644A (en) * 2009-12-23 2011-07-06 Haomamedica Ltd 1,4-Dihydro-1,4-dioxonaphtalene derivatives for the treatment of osteoporosis
US8088395B2 (en) 2004-01-21 2012-01-03 Indiana State University Phytol derived immunoadjuvants and their use in vaccine formulations
WO2012080519A1 (fr) * 2010-12-17 2012-06-21 Vitak B.V. Utilisation de la vitamine k pour maintenir le poids et contrôler le poids
US8354129B2 (en) 2000-05-12 2013-01-15 Nattopharm ASA Vitamin containing product
EP1728507B2 (fr) † 2005-06-03 2014-11-12 NattoPharma ASA Compositions pour le traitement ou la prevention des maladies cardiovasculaires

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL78611A0 (en) * 1986-04-23 1986-08-31 Yeda Res & Dev Production of polyprenoid and ubiquinone-type compounds
EP0636598B1 (fr) * 1993-07-26 1997-04-09 Eisai Chemical Co., Ltd. Procédé pour la préparation des dérivés de naphthoquinone et des produits intermédiaires pour leur préparation
GB9713620D0 (en) * 1997-06-28 1997-09-03 Boots Co Plc Composition
ES2286070T3 (es) * 2000-05-12 2007-12-01 Nattopharma Asa Producto alimenticio que contiene vitamina k2.

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8354129B2 (en) 2000-05-12 2013-01-15 Nattopharm ASA Vitamin containing product
US8728553B2 (en) 2000-05-12 2014-05-20 Nattopharma Asa Vitamin containing product
EP1556025A1 (fr) 2002-08-30 2005-07-27 Vitak Bv Compositions contenant de la vitamine k pour le traitement ou la prevention du raidissement des arteres du a l'age
US12144785B2 (en) 2002-08-30 2024-11-19 Nattopharma As Composition of vitamin K and vitamin D for treating or preventing cardiovascular disease
WO2004019923A1 (fr) * 2002-08-30 2004-03-11 Vitak Bv Compositions contenant de la vitamine k pour le traitement ou la prevention du raidissement des arteres du a l'age
US9364447B2 (en) 2002-08-30 2016-06-14 Nattopharma Asa Compositions for treating or preventing cardiovascular disease
US8088395B2 (en) 2004-01-21 2012-01-03 Indiana State University Phytol derived immunoadjuvants and their use in vaccine formulations
EP1728507B2 (fr) † 2005-06-03 2014-11-12 NattoPharma ASA Compositions pour le traitement ou la prevention des maladies cardiovasculaires
GB2476644B (en) * 2009-12-23 2012-11-14 Haomamedica Ltd 1,4-Dihydro-1,4-dioxonaphtalene derivatives for the treatment of osteoporosis
US8895624B2 (en) 2009-12-23 2014-11-25 Haoma Medica Ltd. Treatment of osteoporosis
US9622989B2 (en) 2009-12-23 2017-04-18 Haoma Medica Limited Treatment of osteoporosis
GB2476644A (en) * 2009-12-23 2011-07-06 Haomamedica Ltd 1,4-Dihydro-1,4-dioxonaphtalene derivatives for the treatment of osteoporosis
WO2012080519A1 (fr) * 2010-12-17 2012-06-21 Vitak B.V. Utilisation de la vitamine k pour maintenir le poids et contrôler le poids

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WO2003013420A3 (fr) 2003-11-06
EP1414387A2 (fr) 2004-05-06

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