WO2015159153A1 - Nouveaux bisphosphonates et leur utilisation - Google Patents

Nouveaux bisphosphonates et leur utilisation Download PDF

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WO2015159153A1
WO2015159153A1 PCT/IB2015/000858 IB2015000858W WO2015159153A1 WO 2015159153 A1 WO2015159153 A1 WO 2015159153A1 IB 2015000858 W IB2015000858 W IB 2015000858W WO 2015159153 A1 WO2015159153 A1 WO 2015159153A1
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acid
aminomethylenebisphosphonic
aminomethylenebisphosphonic acid
nmr
mhz
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PCT/IB2015/000858
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English (en)
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Ewa CHMIELEWSKA
Paweł KAFARSKI
Joanna Wietrzyk
Katarzyna KEMPIŃSKA
Zdzisław KIEŁBOWICZ
Anita PIĄTEK
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Wrocławskie Centrum Badań Eit+ Sp. Z O.O.
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Publication of WO2015159153A1 publication Critical patent/WO2015159153A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/59—Hydrogenated pyridine rings

Definitions

  • the subject of the present invention are novel diphosphonic acids or their physiologically admissible salts as well as their use.
  • the present invention relates to novel N-substituted aminomethylenebisphosphonates exhibiting anti-osteoporotic properties shown using an MTT assay that measures the percent the inhibition of the proliferation of mouse macrophage-like cell line J744E as well as in an in vivo assay.
  • improve bone resorption denotes the degree of bone resorption which exceeds the degree of bone creation either locally or throughout the skeleton.
  • improve bone resorption can be connected with the formation of bone of improper structure.
  • the term "inhibition of bone resorption” as used herein denotes the treatment or prevention of bone resorption through the direct or indirect alteration of osteoclast formation or activity.
  • the inhibition of bone resorption refers to the treatment or prevention of bone loss, particularly the inhibition of the removal of extant bones from the mineral phase and/or organic matrix phase through the direct or indirect alteration of osteoclast formation or activity.
  • Diseases connected with improper bone resorption encompass, without limitation, osteoporosis, Paget's disease as well as hypercalcemia during neoplasmic diseases.
  • osteoporosis a systemic skeletal disease characterised by low bone mass and the loss of bone tissue microstructure, with a subsequent increase in bone friability and susceptibility to breakage. Because osteoporosis, as well as other bone-loss related diseases are chronic diseases, it is thought that appropriate therapy will require substantially chronic treatment.
  • Osteoporosis may also be caused by steroids and is observed in elderly men as well. Osteoporosis may be caused by diseases such as rheumatoid arthritis. It may also be caused by secondary causes, such as glucocorticoid treatment, or by unknown causes, the so-called idiopathic osteoporosis. The methods described herein pertain to the treatment or prevention of improper bone resorption in patients with osteoporosis.
  • the most preferable approach is the stimulation of new tissue formation conducted by osteoblasts or the inhibition of osteoclast activity responsible for bone resorption.
  • Natural substances present in the organism that play such roles i.e. estrogens, vitamin D or parathormone, should not be administered exogenously since at non-physiological doses they possess numerous adverse effects due to their hormonal activity.
  • Bisphosphonates or bisphosphonic acids or their pharmaceutically admissible salts are synthetic analogues of naturally occurring pyrophosphates. Due to their strong affinity for calcium phosphate, in dense bone bisphosphonates strongly bind to minerals that are a part of bone. Pharmacologically active bisphosphonates are well known inhibitors of bone resorption, and are thus useful in the treatment and prophylaxis of diseases connected with improper bone resorption, particularly osteoporosis, Paget's disease, malignant hypercalcemia and metabolic bone diseases.
  • osteoclasts are responsible for bone loss during the bone resorption process
  • bisphosphonates are selective inhibitors of bone resorption which occurs via osteoclast activity, which makes them significant therapeutic compounds for the treatment of various generalised or local bone disorders connected to improper bone resorption.
  • H. Fleisch Bisphosphonates In Bone Disease, From Laboratory To The Patient, 2'nd ed, Parthenon Publishing (1995).
  • alendronate there is much available preclinical and clinical data, relating to the strong bisphosphonate, alendronate.
  • Other bisphosphonates such as risedronate, tiludronate, ibandronate and zolendronate, possess many properties in common with alendronate, including considerable potency as inhibitors of bone resorption by osteoclasts.
  • etidronate An older bisphosphonate compound, etidronate, also inhibits bone resorption. However, in contrast to stronger bisphosphonates, etidronate disrupts mineralisation and may initiate osteomalacia, a state of adversely decreased bone mineralisation. See: B. F. Boyce, L. Smith, I. Fogelman, E. Johnston, S. Ralston, I. T. Boyle. Focal osteomalacia due to low-dose diphosphonate therapy in Paget's disease. Lancet. 1984, 8381 : 821-824 as well as C. J. Gibbs, J. E. Aaron, M. Peacock Osteomalacia in Paget's disease treated with short term, high dose sodium etidronate. Br. Med. J.
  • Intravenous injection was used to bypass the bioavailability problem.
  • IV is expensive and inconvenient, particularly when the patient must receive repeating infusions lasting for several hours each.
  • Bisphosphonates as pharmaceuticals are described, for example, in the European patents EP-A-170228, EP-A-197478, EP-A-22751 , EP-A-252504, EP-A-252505, EP-A-258618, EP- A-350002, EP-A-273190, WO-A-90/00798 as well as US 4666895, US 4719203, EP-A- 252504, EP-A-252505, US 4777163, US 5002937, US 4971958 and others.
  • Cycloheptylaminomethylene-1 ,1- bisphosphonic acid, YM 175, is described in US patent 4970335.
  • a particular goal of the present invention is to deliver novel compounds useful in the inhibition of bone resorption, particularly in the treatment of osteoporosis.
  • the subject of the present invention is a compound defined by the formula 1 or its pharmaceutically admissible salt
  • R denotes: an alkyl, aryl, heteroaryl or methylenebisphosphonate.
  • a compound of the present invention is N- piperidyl)piperazinyl]aminomethylenebisphosphonic acid (37).
  • the subject of the present invention is a compound defined by the formula 2 pharmaceutically admissible salt
  • R denotes: an aryl, heteroaryl or aryl substituted methylenebisphosphonate.
  • the subject of the present invention is also the use of a compound defined above in the production of a drug for inhibiting bone resorption, preferably for the prevention or treatment of osteoporosis.
  • Aminomethylenebisphosphonates substituted on the amino nitrogen one or two simple or branched aliphatic groups: alkyl, cycloalkyl, heterocycloalkyl, phenyl, substituted phenyl, heterocyclic aromatic substituents (Figure 1) as well as di(aminomethylenebisphosphonates) placed on an aromatic, cycloaliphatic or heteroaliphatic skeleton ( Figure 2) are characterised in that they exhibit anti-osteoporotic properties, as shown using an MTT assay which measures the percent of inhibition of the proliferation of the murine macrophage-like cell line J744E as well as in an in vivo assay performed on sheep.
  • the term "bisphosphonate” denotes a compound containing two C-P bonds.
  • bisphosphonate as used in the description in relation to medicinal substances according to the present invention also encompasses bisphosphonates, bisphosphonic acids and diphosphonic acid, as well as their salts and derivatives.
  • the use of a specific nomenclature in relation to a bisphosphonate or bisphosphonates does not limit the scope of the present invention, unless otherwise denoted.
  • Compounds according to the present invention are useful for inhibiting bone resorption as well as for the treatment and prophylaxis of improper bone resorption as well as the states connected thereto.
  • Such states encompass both generalised and local bone loss.
  • the formation of bones of improper structure, as in Paget's disease may be connected with improper bone resorption.
  • the term "generalised bone loss” denotes bone loss at many sites of the skeleton or throughout the skeletal system.
  • local bone loss denotes the loss of bone in one or many particular sites defined as sites on the skeleton.
  • the present invention also discloses a method of producing novel acids of aminomethylenebisphosphonates with the general formulas shown in Figure 1 and Figure 2, wherein R 1 denotes a hydrogen atom, a simple or branched alkyl, cycloalkyl, heterocycloalkyl, phenyl, substituted phenyl, or heterocyclic aromatic substituent, R 2 denotes a hydrogen atom, a simple or branched alkyl or cycloalkyl and R 1 and R 2 along with a nitrogen atom constitute a fragment of the heterocycloalkyl ring, whereas R 3 is a benzene or cycloalkyl skeleton or with two nitrogen atoms constitutes a fragment of a piperazine ring and is based on the fact that an aliphatic amine, an alkyl orthoformate, preferably a triethyl orthoformate and a dialkyl phosphite, preferably diethyl phosphite, is heated to boiling
  • Ri denotes a hydrogen atom, a simple or branched alkyl, cycloalkyl, heterocycloalkyl, phenyl, substituted phenyl, heterocyclic aromatic substituent
  • R 2 denotes a hydrogen atom, alkyl or cycloalkyl
  • Ri and R 2 along with a nitrogen atom constitute a fragment a heteocycloalkyl ring
  • R3 is a benzene or cycloalkyl skeleton or, with two nitrogen atoms, it constitutes a fragment of a piperazine ring.
  • bisphosphonate and bisphosphonates in the meaning used herein in relation to therapeutic factors may also encompass diphosphonates, biphosphonic acids, diphosphonic acids, as well as their pharmaceutically admissible salts and derivatives.
  • Preferable salts are salts selected from a group encompassing sodium, potassium, calcium, magnesium and ammonium salts.
  • Non-limiting examples of derivatives encompass those selected from a group encompassing esters, hydrates and amides.
  • “Pharmaceutically admissible” as used herein denotes that salts and derivatives of bisphosphonates have the same pharmacological properties as the free acid they are derived from, and are admissible from the point of view of toxicity.
  • osteoblasts bone building cells
  • osteoclasts bone degrading cells
  • Osteoblasts arise from mesenchymal stem cells
  • osteoclasts are polynuclear cells derived from mononucleated hematopoietic marrow precursors of the monocyte-macrophage line. See: Barengolts E.I., Berman M., Kukreja S.C., Kouznetsova T., Lin C, Chomka E.V.: Osteoporosis and coronary atherosclerosis in asymptomatic postmenopausal women. Calcif. Tissue Int. 1998, 62: 209- 213 as well as W. S.
  • Osteoclast precursor cells possess the transmembrane receptor RANK (receptor activator of nuclear factor ⁇ ), which activate nuclear factor ⁇ , which transmits the signal into the nucleus that activates the genetic expression cascade that causes the differentiation of preosteoclasts into osteoclasts.
  • RANK transmembrane receptor RANK
  • Aminobisphosphonates (alendronate, pamidronate and risedronate) enhance macrophage apoptosis by inhibiting the intracellular isoprenylation of signal proteins, whereas bisphosphonates lacking nitrogen such as clodronate, undergo an intracellular transformation into the cytotoxic adenosine 5'(beta-gammadichloromethylene) triphosphate.
  • bisphosphonates lacking nitrogen such as clodronate
  • Procedure A general synthesis procedure of compounds according to the present invention: a primary or secondary aliphatic amine (0,03 moles), and trialkyl orthoformate (0,03 moles), preferably triethyl orthoformate and a dialkyl phosphite, (0,06 moles) preferably diethyl phosphite, were heated to a temperature of ⁇ 100°C under a recirculating cooler for 12 hours. The alcohol formed was evaporated off in a rotating evaporator. The raw reaction product was hydrolysed by heating it with 20 cm 3 6N hydrochloric acid until boiling. The hydrolysis was conducted for 8 hours. After cooling the reaction mixture to room temperature the remaining acid was removed by evaporation.
  • Procedure B general synthesis procedure of compounds according to the present invention - parallel synthesis: a primary or secondary aliphatic amine (0,03 moles), trialkyl orthoformate preferably triethyl orthoformate (0,032 moles) and a dialkyl phosphite, preferably diethyl phosphite (0,062), were heated and at the same time stirred at a temperature of ⁇ 130°C on a heating plate (125°C in a reaction medium) on a Carousel apparatus, Radleys, for 15 hours. The mixture was cooled, and the ethyl alcohol formed was evaporated off in a rotating evaporator. The resulting aminomethylenebisphosphonic acid ester was not purified.
  • the raw reaction product was hydrolysed by heating it with 20 cm 3 6N hydrochloric acid at boiling temperature (1 10°C). The hydrolysis was conducted for 10 hours. After cooling, the volatile components were removed from the mixture using a rotating evaporator. The resulting oil was dissolved in water, destained with active charcoal and purified by hot crystallisation from an appropriately selected system (i.e. water, water/ethanol, water/methanol, ethanol/water).
  • Procedure C general synthesis procedure of compounds according to the present invention: an appropriate diamine (0,03 moles), dialkyl phosphite, preferably diethyl phosphite (0, 12 moles) and a trialkyl orthoformate, preferably triethyl orthoformate (0,06 moles), were heated and at the same time stirred at a temperature of 80-120°C for 18-14 hours.
  • the unneeded, volatile components of the reaction mixture were evaporated off, and the remaining, raw product was subjected to hydrolysis in concentrated hydrochloric acid (40-60 ml) for 12 hours.
  • the raw product of the desired tetraphosphonate was purified by crystallisation from water, a mixture of water with methanol or a mixture of water with ethanol.
  • Example 1 aminomethylenebisphosphonic acid (1 ) Methylbenzylamine (0,03 moles, 3,82g) was heated under a recirculating cooler until boiling with an equimolar amount of triethyl orthoformate (0,03m, 4,45 g) and a double amount of diethyl phosphite (0,06 moles, 8,29 g) at a temperature of ⁇ 90°C for 12 h. The ethanol resulting from the reaction was removed in a rotating evaporator. The raw reaction product was hydrolysed by heating it with 20 cm 3 6N hydrochloric acid until boiling. The hydrolysis was conducted for 8 hours at a temperature of 100°C.
  • Example 3 A/-(n-pentyl)aminomethylenebisphosphonic acid (3) was obtained with 41 % yield, melting temp.
  • Example 5 A/-(n-octyl)aminomethylenebisphosphonic acid (5) was obtained with 48% yield, melting temp.
  • Example 13 A/-(iso-pentyl)aminomethylenebisphosphonic acid (13) was obtained with 46% yield, melting temp.
  • Example 21 W- ⁇ -amino-cyclohexylJaminomethylenebisphosphonic acid (20) was obtained with 27% yield, melting temp.
  • Example 37 A/-(4-methylpiperazinyl)aminomethylenebisphosphonic acid was obtained with 31 % yield, melting temp.
  • Example 42 A/-[4-(2-piperidyl)piperazinyl]aminomethylenebis
  • Example 52 A/-(3,5-dichlorophenyl)aminomethylenebisphosphonic acid (46) was obtained with 52% yield, melting temp.
  • Example 55 A/-(4-nitrophenylamino)methylenebisphosphonic acid (47) was obtained with 68% yield, melting temp.
  • Example 77 A/-(3,5-dichloropyrid-4-yl)aminomethylenebisphosphonic acid (69) was obtained with 42% yield, melting temp.
  • Example 81 A/-(4,6-dichloropyrimid-2-yl)aminomethylenebisphosphonic acid (73) was obtained with 51 % yield, melting temp.
  • Example 110 cyclohexylo-1 ,3-di(aminomethylenebisphosphonic acid) (99) was obtained with 42% yield, melting temp.
  • Example 1 12 piperid-1 ,4-yl-di(aminomethylenebisphosphonic acid) (101) was obtained with 42% yield, melting temp.
  • the 96 hour assay was performed using colorimetric methods using flat-bottomed 96-well plates. All of the activities described below were performed in a laminar flow chamber with a class A Bio-hazard rating.
  • the wells were loaded with cells from the in vitro culture suspended in 100 ⁇ culture medium, at a rate of 5x10 4 /ml.
  • the plates were incubated at 37 ° C, in a moist environment saturated with 5% CO2. 24 hours later, the wells were supplemented with another 100 ⁇ of medium (cell proliferation control) or medium containing the evaluated compounds.
  • the initial solutions of the tested compounds (1 mg/ml) were prepared ex tempore to each experiment, dissolving 1 mg of the preparation in 1 ml culture medium, which was also the solvent for subsequent dilutions.
  • the control (negative sample) was a solution containing the culture medium.
  • the positive sample consisted of cells suspended in culture medium.
  • the measured absorbance values were recalculated into values demonstrating the inhibition of proliferation.
  • the measure of cell apoptosis was possible using the nick translation assay, which turned out to be a preferable method.
  • IC50 values the dose which inhibits proliferation in 50% of a cell population
  • percent inhibition of proliferation were determined for each compound.
  • the accepted criterion for accepting the activity of novel compounds in in vitro screening assays is an IC50 level of no more than 4 mg/ml. See R. I. Geran, N. H. Greenberg, M. M. Macdonald, A. M. Schumacher, B. D. Abbot. Protocols for screening chemical agents and natural products against animal tumours and other biological systems. Cancer Chemother. Rep. 1972, 32:, 59-61.
  • the precise dosage of a bisphosphonate will differ depending on the dosage regime, the strength of activity following the oral administration of a selected bisphosphonate, age, size, sex and condition of the mammal, the nature and severity of the treated disorder and other significant medical and physical factors.
  • an appropriate bisphosphonate amount is selected so as to obtain an inhibitory effect against bone resorption, meaning an amount of bisphosphonate is administered which inhibits bone resorption.
  • An effective dose of a bisphosphonate is usually contained in the range from 1 ,5 to about 6000 (mg/kg body mass, and preferably from about 10 to about 2000 mg/kg body mass).
  • the experimental group consisted of animals which were given the novel compounds, whereas the control group was given incadronate.
  • the control group was given incadronate.
  • the animals were pre-medicated with xylazine at a dose of 0.25mg/kg bm.
  • methylprednisolone After 18 days post-operation, we initiated the administration methylprednisolone at a dose of 250 mg/ewe BM. Before administering a drug we performed a radiological evaluation of both hind legs in two planes, lateral and sagittal, in order to visualise the bone structure.
  • methyloprednisolone was administered every 20 days at a decreased dose of 150 mg/ewe. In total, the ewes received the steroid drug 4 times. Each time before the drug was administered, we performed blood haematological and biochemical tests to monitor changes in blood parameters.
  • the bone biopsies were placed in physiological saline in test tubes and sent for CMT studies.
  • Computer microtomography analyses were performed at the Orthopedic Clinic of the Wroclaw Medical University.
  • CMT is a non-invasive method which makes it possible to reconstruct the internal structure of the bone and precisely analyse it in three dimensions. See M. L. Bouxein, S. K. Boyd, B. A. Christansen, R. E. Guldberg, K. J. Jepsen, R, Muller. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J. Bone. Mineral. Res. 2010, 25: 1468-1486.
  • the TEM analyses were performed using the electron microscope of the Laboratory of Electron Microscopy of the Biological University of Wroclaw.
  • a photograph of a section of the humerus of an animal treated with compound 79 is shown in Fig. 1.
  • At the periphery of the osteoresorption islets there are numerous osteoblasts that participate in the repair process. This, thus, leads to the formation of new osteons, initially two and three layered ones.
  • In the zone between the osteons there are also intrasystemic layers, which at their polar ends also undergo osteoresorption. This constitutes a site for the formation of novel bone tissue.
  • Fig. 2 represents an image of a femoral section of a ewe treated with compound 79.
  • the histological analysis of HE-stained samples shows forming osteons. At the periphery of the forming osteons, there are numerous resorption cavities. Moreover, the osteoresorptive areas occur between the intrasystemic layers. In the zone between the forming osteons we noted a large accumulation of osteoresorption sites as well as accumulating osteoblasts.
  • FIG. 3 Another example is the photograph shown in Fig. 3 of a humerus section from a ewe treated with compound 5, wherein van Gieson staining shows numerous sites of osteoresorption. At the edges of osteoresorption areas there are primary osteons, usually three and four layered. The continuing osteoresorption relates mainly to intrasystemic layers as well as a small number of osteons.

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Abstract

L'invention concerne de nouveaux acides diphosphoniques ou leurs sels physiologiquement admissibles, ainsi que leur utilisation dans la production d'un médicament pour inhiber la résorption osseuse, pour la prévention ou le traitement de l'ostéoporose.
PCT/IB2015/000858 2014-04-16 2015-04-16 Nouveaux bisphosphonates et leur utilisation WO2015159153A1 (fr)

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