WO1997008178A1 - Novel bisphosphonates, process for their preparation and pharmaceutical compositions containing them - Google Patents

Novel bisphosphonates, process for their preparation and pharmaceutical compositions containing them Download PDF

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WO1997008178A1
WO1997008178A1 PCT/IL1996/000087 IL9600087W WO9708178A1 WO 1997008178 A1 WO1997008178 A1 WO 1997008178A1 IL 9600087 W IL9600087 W IL 9600087W WO 9708178 A1 WO9708178 A1 WO 9708178A1
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compound
formula
compound according
compounds
irregularities
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PCT/IL1996/000087
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WO1997008178B1 (en
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Ivan Sergeievitch Alferiev
Eli Breuer
Gershon Golomb
Asher Ornoy
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Yissum Research Development Company Of The Hebrew University Of Jerusalem
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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
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings
    • 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
    • C07F9/572—Five-membered rings
    • 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
    • C07F9/58—Pyridine rings
    • 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
    • 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
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/65031—Five-membered rings having the nitrogen atoms in the positions 1 and 2
    • 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
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • 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
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • the present invention relates to novel compounds of the general formula
  • Q designates -H or -NR 1 R 2 , where A designates a 5- or 6-membered heterocyclic ring which contains 1, 2 or 3 nitrogen atoms, zero, 1 or 2 oxygen atoms and which may contain a sulfur atom, which contains up to and including 3 double bonds,
  • R 1 and R 2 are independently hydrogen, lower
  • alkyl lower alkenyl, lower alkoxy, (di)alkylaminoalkyl, alkoxyalkyl and where the ring A may be substituted by one or more conventional substituents.
  • the invention further relates to pharmaceutical
  • compositions preferably for oral application, which
  • the invention specifically relates to pharmaceutical
  • compositions have a ring of the 2-aminopyrimidine type.
  • Bone related diseases There are several pathological conditions that involve irregularities in calcium metabolism. Such are some bone related diseases as Paget's desease, osteoporosis as well as osteolysis in bone metastases. Bone
  • metastases present a major problem in many frequently occurring malignancies. Hypercalcemia, resulting from bone resorption, is a common and very important
  • neoplastic cell-induced osteolysis may determine the localization and growth enhancement of the tumor.
  • pathological condition characterized by the deposition for calcium phosphate in a number of clinically
  • bioprostetic heart valve calcification and implanted biomaterial calcification such as bioprostetic and prosthetic heart valves, vascular grafts, LVAD (Left ventricular assist devices), contact lenses and a total artificial heart.
  • LVAD Left ventricular assist devices
  • novel bisphosphonates are useful in the treatment of the following diseases; Osteoporosis (including disuse and
  • Hyperphosphatemia e.g. Diabetes
  • said compounds are useful not only for direct treatment of various diseases but also for treatment of the symptoms of the diseases (e.g.
  • the compounds according to the present invention are also useful as diagnostics (e.g. Nuclear Medicine).
  • the compounds according to the present invention may possess also industrial applications which are listed below (R.L. Hilderbrand. The Role of Phosphonates in Living Systems, Chapter 7, page 172, CRC Press).
  • Adhesives Agents for extraction, concentration, and purification of uranium, thorium, and plutonium;
  • Antioxidants Antistatic agents; Blowing agents;
  • Crystallization inhibitors Crystallization inhibitors; Dentifrice compositions; Deodorants; Detergent additives; Detergents for cleaning metal surfaces; Dye modifiers; Flame
  • Fire retardants for synthetic fibers Flotation agents; Fuel additives; Gelling agents; Hardening oil
  • Viscosity modifiers Wood fireproofing agents.
  • Bisphosphonates are a relatively new class of drugs that have been developed for use in various metabolic processes.
  • the currently used bisphosphonates all belong to the geminal type, in which the two phosphoryl groups are bound to the same carbon ("P-C-P"), and therefore may be viewed as pyrophosphate analogs in which the oxygen between the two phosphorus atoms is replaced by a carbon. From the results obtained in various clinical studies using bisphosphonates it appears that there still is a need for compounds which have better oral bioavailability, greater margin between the bone
  • the present invention relates to novel compounds of the general formula
  • R 1 and R 2 are independently hydrogen, lower alkyl, lower alkenyl, lower alkoxy, alkoxyalkyland where the ring A may be substituted by one or more
  • A designates a 5- or 6-membered heterocyclic ring which contains 1, 2 or 3 nitrogen atoms, zero, 1 or 2 oxygen atoms and which may contain a sulfur atom, which contains up to and including 3 double bonds,
  • the invention further relates to pharmaceutical
  • compositions preferably for oral application, which contain an effective quantity of one or more compounds of the above formula.
  • the invention specifically relates to pharmaceutical compositions for the prevention and treatment or irregularities of calcium metabolism in mammals, and especially in humans.
  • compositions have a ring of the 2-aminopyrimidine type.
  • the invention further relates to a process for the production of such bis-phosphonate compounds.
  • a suitable vinylidene-bis-phosphonic acid hydrate, or corresponding higher homologue is reacted with a suitable heterocyclic compound, as herein defined, and purifying the product.
  • the invention further relates to pharmaceutical
  • the main route of application is the oral route and unit dosage forms for oral administration contain for about 1 mg/kg to about 30 mg/kg of the active compound, and preferably from about 3 mg/kg to about 10 mg/kg of such bisphosphonate compound.
  • One-month-old rats of the Sabra strain (weighing 90-100 g) were treated daily (for 2 weeks) by subcutaneous injections with substances No. ISA 13-1, (6 mg/kg).
  • Controls were treated with saline (0.1 ml/100g body weight). After 2 weeks, the animals were sacrified. One tibia was dried weighed, ashed at 850°C and the Ca, P and Mg contents were determined. The other tibia was fixed in 10% buffered formaldehyde, decalcified in 4% formic acid, and embedded in glycol methacrylate. Two-three micron thick longitudinal sections were stained by toluidine blue and examined (semiquantitative analysis) by light microscopy. The results of chemical analysis fo the bones show that compound ISA 13-1 increased significantly (by 20%-40%) bone weight, ash weight and mineral content. Microscopical examination of the tibias showed a marked increase in the amount (both length and number) of metaphysaal bone trabeculas following treatment with substance ISA 13-1.
  • Bisphosphonate ISA 13-1 was administered orally daily for 2 weeks by intragastric intubation to one month old rate weighing 100 g. in doses of 5 or 30 mg/kg.
  • Pamidronate was given orally in identical doses.
  • Each group consisted of 8 rats. After 2 weeks the animals were sacrified and blood was removed for Ca and alkaline phosphates determination. The tibias were removed. One bone was used for the determination of ash weight, Ca, P, and Mg content, while other was fixed and embedded in glycol-methacrylate and the longitudinal sections were examined by light microscopy.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Bisphosphonate compounds, their preparation and pharmaceutical compositions which contain such compounds as active ingredients. Such compositions are generally administered per os and they are effective for treating irregularities of the calcium metabolism. Preferred compounds have a 2-aminopyrimidine type ring. Similar unsubstituted and substituted heterocyclic compounds were found to have a similar activity.

Description

NOVEL BISPHOSPHONATES , PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
The present invention relates to novel compounds of the general formula
Figure imgf000003_0001
where Q designates -H or -NR1R2, where A designates a 5- or 6-membered heterocyclic ring which contains 1, 2 or 3 nitrogen atoms, zero, 1 or 2 oxygen atoms and which may contain a sulfur atom, which contains up to and including 3 double bonds,
where R1 and R2 are independently hydrogen, lower
alkyl, lower alkenyl, lower alkoxy, (di)alkylaminoalkyl, alkoxyalkyl and where the ring A may be substituted by one or more conventional substituents.
The invention further relates to pharmaceutical
compositions, preferably for oral application, which
contain an effective quantity of one or more compounds of the above formula.
The invention specifically relates to pharmaceutical
compositions for the prevention and treatment or
irregularities of calcium metabolism in mammals, and
especially in humans.
Other and further aspects of the invention will become apparent hereinafter. Preferred compounds and
compositions have a ring of the 2-aminopyrimidine type. BACKGROUND OF THE INVENTION
There are several pathological conditions that involve irregularities in calcium metabolism. Such are some bone related diseases as Paget's desease, osteoporosis as well as osteolysis in bone metastases. Bone
metastases present a major problem in many frequently occurring malignancies. Hypercalcemia, resulting from bone resorption, is a common and very important
complication of malignancy, causing most distressful symptoms, such as severe pain, spontaneous fractures, and may lead to a metabolic coma and death. Moreover, neoplastic cell-induced osteolysis may determine the localization and growth enhancement of the tumor. (G.R. Mundy, Bone, S. supp. 1, s9-5 16 (1987); Calcium in Biological Systems, R.P. Rubin, G.B. Weiss, and J.W.
Putney, Jr., eds. Plenum Press, N.Y. (1985)). Ectopic calcification is a seemingly opposite type of
pathological condition, characterized by the deposition for calcium phosphate in a number of clinically
important diseases as, for example, artherosclerosis, kidney and renal calculus, arthritis, and bioprostetic heart valve calcification, and implanted biomaterial calcification such as bioprostetic and prosthetic heart valves, vascular grafts, LVAD (Left ventricular assist devices), contact lenses and a total artificial heart.
The novel bisphosphonates, according to the present invention are useful in the treatment of the following diseases; Osteoporosis (including disuse and
postmenopausal osteoporosis); Hypercalcemia of
Malignancy, (Direct) anticancer effect; Heterotopic Ossification (Hip Arthroplasty, Spinal cord injury;
Myositis Ossifications); Page's disease;
Hyperphosphatemia (e.g. Diabetes). It can be seen that said compounds are useful not only for direct treatment of various diseases but also for treatment of the symptoms of the diseases (e.g.
Hyperphosphatemia or Hypercalcemia).
The compounds according to the present invention are also useful as diagnostics (e.g. Nuclear Medicine).
The compounds according to the present invention may possess also industrial applications which are listed below (R.L. Hilderbrand. The Role of Phosphonates in Living Systems, Chapter 7, page 172, CRC Press).
Adhesives; Agents for extraction, concentration, and purification of uranium, thorium, and plutonium;
Antioxidants; Antistatic agents; Blowing agents;
Catalysis; Corrosion inhibitors; Coupling agents;
Crystallization inhibitors; Dentifrice compositions; Deodorants; Detergent additives; Detergents for cleaning metal surfaces; Dye modifiers; Flame
retardant polymers; Flame retardants for textiles;
Fire retardants for synthetic fibers; Flotation agents; Fuel additives; Gelling agents; Hardening oil
composites; Heat and light stabilizers; Hydraulic fluid additives; Ion exchange resins; Lubricants;
Photography; Plasticizers; Polyester, polyethylene, and polycarbonate discoloration inhibitors;
Polyurethane additives; Rayon additives; Resin and plastic additives; Scale inhibitors; Settling
retardants; Sequestering agents; Solvent extraction; Suspending agents; Synthetic fiber preparation;
Viscosity modifiers; Wood fireproofing agents. Bisphosphonates are a relatively new class of drugs that have been developed for use in various metabolic
diseases of bone, the target being excessive bond resorption and inappropriate calcification and
ossification. (M.D. Francis and R.R. Markodam, in "The Role of Phosphonates in Living Systems", R.L.
Hilderbrand, ed. CRC Press, Boca Raton, Fla, 983, pp. 55-96; H. Fleisch, Bone, 1987, 8, Supp. 1, s23-s28). Recently, there have been reports of encouraging
clinical trials utilizing bisphosphonates to treat hypercalcemia in patients with breast cancer, myeloma, and bronchial carcinoma related osteolytic metastases, in addition to the established usage of bisphosphonates in Paget's disease and for diagnostic purposes in bone mapping. However, bisphosphonate therapy is frequently accompanied by severe side effects. Bisphosphonates have been also found highly potent both in inhibiting bioprosthetic heart valve calcification, and in
experimental arteriosclerosis, however, this was
accompanied by severe adverse effects on bone
development and overall sematic growth.
The currently used bisphosphonates all belong to the geminal type, in which the two phosphoryl groups are bound to the same carbon ("P-C-P"), and therefore may be viewed as pyrophosphate analogs in which the oxygen between the two phosphorus atoms is replaced by a carbon. From the results obtained in various clinical studies using bisphosphonates it appears that there still is a need for compounds which have better oral bioavailability, greater margin between the bone
resorption inhibiting effect and that inhibiting
mineralization, without an increase is toxicity. According to the present invention it was found that by linking nitrogen containing heterocyclics to the side chain of bisphosphonates highly active compounds are obtained. The favorable effect on bone turnover of such new compounds was uniquely associated with the net increase of normal bone.
Compounds belonging to this group have also shown to possess significantly improved bioavailibility.
SUMMARY OF THE INVENTION
The present invention relates to novel compounds of the general formula
Figure imgf000007_0001
where R1 and R2 are independently hydrogen, lower alkyl, lower alkenyl, lower alkoxy, alkoxyalkyland where the ring A may be substituted by one or more
conventional substituents.
where A designates a 5- or 6-membered heterocyclic ring which contains 1, 2 or 3 nitrogen atoms, zero, 1 or 2 oxygen atoms and which may contain a sulfur atom, which contains up to and including 3 double bonds,
where hydrogen, lower alkyl, lower alkenyl, or lower alkoxy (di)alkylaminoalkyl, alkoxyalkyl, and where the ring A may be substituted by one or more conventional substituents.
The invention further relates to pharmaceutical
compositions, preferably for oral application, which contain an effective quantity of one or more compounds of the above formula. The invention specifically relates to pharmaceutical compositions for the prevention and treatment or irregularities of calcium metabolism in mammals, and especially in humans.
Other and further aspects of the invention will become apparent hereinafter. Preferred compounds and
compositions have a ring of the 2-aminopyrimidine type.
The invention further relates to a process for the production of such bis-phosphonate compounds.
Advantageously a suitable vinylidene-bis-phosphonic acid hydrate, or corresponding higher homologue, is reacted with a suitable heterocyclic compound, as herein defined, and purifying the product.
The invention further relates to pharmaceutical
compositions for regulating the calcium metabolism of mammals, and especially humans, which contain as active ingredient a compound according to the present
invention. The main route of application is the oral route and unit dosage forms for oral administration contain for about 1 mg/kg to about 30 mg/kg of the active compound, and preferably from about 3 mg/kg to about 10 mg/kg of such bisphosphonate compound.
The invention is illustrated by means of a detailed example, it being understood that on the basis of this example it is possible to prepare a wide variety of compounds as herein described.
Preparation of 2-(2-aminopyrimidinio)-ethylidene-1,1-bis-phosphonic acid betaine (ISA 13-1, 1).
Figure imgf000008_0001
A mixture of vinylidene-bis-phosphonic acid hydrate 10.0g, containing 9.40g, 50.0 mmol of anhydrous acid), 2-aminopyrinidine (10.0g, 105.0 mmol) and water (6 ml) was placed on a bath with temperature 100°C and heated with stirring for 80 mins. The yellow brown mixture was diluted with water (200 ml), decolorized with charcoal and, after additional dilution with water to 600 ml, passed through a column with cationite Dowex-50, H± form. The eluate was concentrated in vacuo to a crystalline slurry (32g), diluted with methanol (40 ml) and allowed to stand at room temperature for complete crystallization with periodical rubbing. The crystals of I were filtered off, washed with a mixture of
methanol (20 ml) and water (10 ml), then with methanol and air-dried. Yield of I was 12.41 g (88% based on vinylidene-bis-phosphonic acid). The product was purified by dissolving in water (600 ml) at 50 - 60°C and the following concentration in vacuo. 1H-NMR (D2O + Na2CO3, pH ca. 7), 6, ppm; 2.20
(tt, 1H, CH, JPH - 21 Hz, JHH - 6 Hz), 4.42 (td, 2H,
CH3, JPH - 14 Hz, JHH - 6 Hz), 6.95 (dd, 1H, H5, J1
- 7 Hz, J2 - 5 Hz), 8.31 (dd, 1H, H4, J1 - 7 Hz, J2 - 1 Hz), 8.62 (dd, 1H, H6, J1 - 5 Hz, J2 - 1 Hz) 31p
NMR (D2O + Na2CO3, pH ca. 7), 6, ppm; 15.3 (dt, Jd
- 21 Hz, Jt - 14 Hz.
Additional compounds prepared by the same method:
2-(2-methylaminopyrimidinio)-ethylidene-1,1-bisphosphonic acid obtained from 2-methylaminopyrimidine in 98% isolated yield. NMR: P-31 15.4 ppm (double triplet, J = 22 Hz, (d) J = 14 Hz (t)).
Proton: 2.42 (1H, tt, J = 22 Hz, J = 6 Hz); 3.12 (3H, s); 4.50 (2H, td, J = 14 Hz (t), J = 6 Hz (d); 7.00 (1H, dd, J = 6 Hz, and J = 5 Hz); 8.41 (1H, dd J = 6 Hz, and J = 2 Hz); 8.79 (1H, dd J = 5 Hz, and J = 2
Hz).
Figure imgf000010_0001
2-(2-aminothiazolic)ethylidene-1,1-bisphosphonic acid obtained from 2- aminothiazole in 95% isolated yield.
NMR: P-31 15.2 ppm (double triplet, (J = 21 Hz (d), J 14 Hz (t).
Figure imgf000010_0002
2-(2-Aminopyridinio)-ethylidene-1,1-bisphosphonic acid betaine:
Figure imgf000010_0003
2-(3-Hydroxypiperidinyl)-ethylidene-1,1-bisphosphonic acid:
Figure imgf000010_0004
2-(1-Imidazolyl)-ethylidene-1,1-bisphosphonic acid:
Figure imgf000011_0001
2-(1-Pyrrolidiny1)-ethylidene-1,1-bisphosphonic acid:
Figure imgf000011_0002
2-(3-Methyl-1-imidazolio)-ethylidene-1,1-bisphosphonic acid betaine:
Figure imgf000011_0003
2-(2-Methyl-1-pyraazolio)-ethylidene-1,1-bisphosphonic acid betaine:
Figure imgf000011_0004
In a similar manner, with a variety of unsubstituted and substituted heterocyclic compounds, instead of 2-amino-pyrimidine, there were prepared in an analogous manner corresponding compounds which were purified as set out in Example 1. Biological Experiments - Subcutaneous Administration.
One-month-old rats of the Sabra strain (weighing 90-100 g) were treated daily (for 2 weeks) by subcutaneous injections with substances No. ISA 13-1, (6 mg/kg).
Controls were treated with saline (0.1 ml/100g body weight). After 2 weeks, the animals were sacrified. One tibia was dried weighed, ashed at 850°C and the Ca, P and Mg contents were determined. The other tibia was fixed in 10% buffered formaldehyde, decalcified in 4% formic acid, and embedded in glycol methacrylate. Two-three micron thick longitudinal sections were stained by toluidine blue and examined (semiquantitative analysis) by light microscopy. The results of chemical analysis fo the bones show that compound ISA 13-1 increased significantly (by 20%-40%) bone weight, ash weight and mineral content. Microscopical examination of the tibias showed a marked increase in the amount (both length and number) of metaphysaal bone trabeculas following treatment with substance ISA 13-1.
The most important microscopical finding is the fact that the new substance did not induce rickets. Its antiresorptive effect resulted in a net increase of normal fully mineralized metaphyseal bone trabeculae. This fact indicates that ISA 13-1 is a much more potent compound/drug than Pamidronate or any related
bisphosphonate.
In addition, there was no significant change in the blood levels of Ca in animals treated by ISA 13-1 as compared to controls. There was no clinical signs of toxicity. Oral Administration
Bisphosphonate ISA 13-1 was administered orally daily for 2 weeks by intragastric intubation to one month old rate weighing 100 g. in doses of 5 or 30 mg/kg. In parallel, Pamidronate was given orally in identical doses. Each group consisted of 8 rats. After 2 weeks the animals were sacrified and blood was removed for Ca and alkaline phosphates determination. The tibias were removed. One bone was used for the determination of ash weight, Ca, P, and Mg content, while other was fixed and embedded in glycol-methacrylate and the longitudinal sections were examined by light microscopy.
The results of the chemical studies showed that ISA 13-1 at the higher dose significantly increased bone and ash weight, and Ca and Mg content. The lower doses of ISA 13-1 had no effect on bone mineral content, but
increased serum Ca and alkaline phosphatase.
Pamidronate in the higher dose of 30 mg/kg also
increased bone ash weight and Ca content while 5 mg/kg had no effect.
Significent histological changes of the tibias were induced by ISA 13-1 in both doses. There was a
significant increase in the length of metaphyseal bone trabeculas and a very significant increase in the amount of bone as opposed to bone marrow. There was also a slight increase in the amount of cartilage in the metaphysis, implying slight rickets. Pamidronate in both doses also increased the length of the metaphyseal trabeculas but they were mainly composed of calcified cartilage without any significant increase in the amount of bone (when compared to bone marrow). Pamidronate also decreased the height of the growth plate, mainly because of a reduction in the amount of hypertrophic cartilage in the lower part of the growth plate. This may imply some direct negative effect of Pamidronate on the growth apparatus of long bones. In conclusion, substance ISA 13-1 seems to be very
effective orally in increasing the amount of bone in young growing rats.
A number of analogous heterocyclic nitrogen-containing compounds were evaluated as to their biological activity and the results demonstrated a similar degree of activity.

Claims

CLAIMS :
1. A compound of the general formula
where Q designates -H or -NR1R2,
Figure imgf000015_0002
where A designates a 5- or 6-membered heterocyclic ring which contains 1, 2 or 3 nitrogen atoms, zero, 1 or 2 oxygen atoms and which may contain a sulfur atom, which contains up to and including 3 double bonds,
where R1 and R2 are independently hydrogen, lower alkyl, lower alkenyl, lower alkoxy, (di)alkylaminoalkyl, alkoxyalkyl and where the ring A may be substituted by one or more conventional substituents.
2. A compound according to claim 1, where A
designates a pyrroline, pyrrolidine, pyrazole,
pyrazoline, pyrazolidine, imidazole, triazole, pyridine, thiazole, oxazole, isoxazole, pyrazine, pyridazine and their partially or fully reduced derivatives, which are substituted as defined in claim 1.
3. A compound according to claim 1, of the formula
Figure imgf000015_0001
where R1 and R2 are a hydrogen, loweralkyl, lower alkoxy, alkoxyalkyl, (di)alkylaminoalkyl, lower alkynyl, and where the pyrimidine ring may be substituted by one or more conventional substituents.
4. A compound according to claim 1, where the -NR1R2 group is in the 2-position.
5. A compound according to claim 1 of the formula:
Figure imgf000016_0001
6. A compound according to claim 1 of the formula:
Figure imgf000016_0002
7. A compound according to claim 1, where A is of the formula:
Figure imgf000016_0003
8. A process for the production of compounds defined in any of claims 1 to 7, which comprise reacting a suitable form of vinylidene-bis-phosphonic acid with the desired heterocyclic compound and purifying the obtained product.
9. A process according to claim 8, for the
production of the compound claimed in claim 5, which comprises reacting vinylidene-bis-phosphonic acid hydrate with amino-pyrimidine, and purifying the product.
10. Process for the production of the compound defined in claim 1, substantially as hereinbefore described.
11. A pharmaceutical composition containing as active ingredient a sufficient quantity of a compound claimed in any of claims 1 to 7.
12. A composition according to claim 11, where the compound is as claimed in claim 5 or 6.
13. A pharmaceutical composition for oral
administration, for the treatment of irregularities of calcium metabolism in mammals, including humans, comprising an effective quantity of a compound claimed in any of claims 1 to 7.
14. A composition according to any of claims 11 to 13, in unit dosage form, containing from about 3 mg/kg to about 10 mg/kg of the active compound.
15. Oral pharmaceutical compositions for the
treatment of irregularities of calcium metabolism, and for the prevention of such irregularities, based on bisphosphonates herein defined, substantially as herein described.
PCT/IL1996/000087 1995-08-23 1996-08-22 Novel bisphosphonates, process for their preparation and pharmaceutical compositions containing them WO1997008178A1 (en)

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IL11504195A IL115041A0 (en) 1995-08-23 1995-08-23 Novel bisphosphonates process for their preparation and pharmaceutical compositions containing them
IL115041 1995-08-23

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US7687482B2 (en) 2006-03-17 2010-03-30 The Board Of Trustees Of The University Of Illinois Bisphosphonate compounds and methods
US7745422B2 (en) 2004-10-08 2010-06-29 The Board Of Trustees Of The University Of Illinois Bisphosphonate compounds and methods for bone resorption diseases, cancer, bone pain, immune disorders, and infectious diseases
US8012949B2 (en) 2004-10-08 2011-09-06 The Board Of Trustees Of The University Of Illinois Bisphosphonate compounds and methods with enhanced potency for multiple targets including FPPS, GGPPS, and DPPS
JP2013542946A (en) * 2010-11-03 2013-11-28 成都雲克薬業有限責任公司 Diphosphonic acid compound, method for preparing diphosphonic acid compound, and use of diphosphonic acid compound

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7745422B2 (en) 2004-10-08 2010-06-29 The Board Of Trustees Of The University Of Illinois Bisphosphonate compounds and methods for bone resorption diseases, cancer, bone pain, immune disorders, and infectious diseases
US8012949B2 (en) 2004-10-08 2011-09-06 The Board Of Trustees Of The University Of Illinois Bisphosphonate compounds and methods with enhanced potency for multiple targets including FPPS, GGPPS, and DPPS
US8071573B2 (en) 2004-10-08 2011-12-06 The Board Of Trustees Of The University Of Illinois, A Body Corporate And Politic Of The State Of Illinois Bisphosphonate compounds and methods for bone resorption diseases, cancer, bone pain, immune disorders, and infectious diseases
US7687482B2 (en) 2006-03-17 2010-03-30 The Board Of Trustees Of The University Of Illinois Bisphosphonate compounds and methods
JP2013542946A (en) * 2010-11-03 2013-11-28 成都雲克薬業有限責任公司 Diphosphonic acid compound, method for preparing diphosphonic acid compound, and use of diphosphonic acid compound

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IL115041A0 (en) 1995-12-08

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