Patent Description:
Parathyroid hormone (PTH) produced in the parathyroid cells has effects on the kidney to enhance calcium (Ca) reabsorption and suppresses reabsorption of inorganic phosphorus (P) from the urine. It also enhances production of activated vitamin D, which promotes intestinal Ca absorption. This hormone further has effects on the bone and promotes bone absorption, by which Ca and P homeostasis is maintained in the body. Secretion of PTH is enhanced in response to decrease in Ca, increase in P and decrease in activated vitamin D in the blood.

In cases of chronic kidney disease, as the renal function decreases with pathological progression, P excretion into the urine is decreased and activated vitamin D is decreased due to failure of vitamin D activation, which result in hyperphosphatemia and hypocalcaemia and leads to elevation of PTH secretion. Persistent stimulation of PTH secretion to the parathyroid glands enhances proliferation of the parathyroid cells, and parathyroid hyperplasia causes excessive secretion of PTH, which results in onset and progression of the condition of secondary hyperparathyroidism (SHPT). In particular, SHPT is frequently caused in patient on dialysis, where excessive PTH induces high turnover bone lesions (fibrous osteitis), increasing Ca and P in the blood. This is problematic in that not only quality of life is decreased but also cardiovascular calcification is caused which leads to poor life prognosis (Non-patent document <NUM>: <NPL>).

While conventional medical treatments for decreasing PTH in the blood employ use of activated vitamin D formulations, their therapeutic effects have been considered insufficient because their administration is limited to the problem of increase in the blood Ca and P concentrations caused by enhancement of the intestinal absorption.

A recently launched oral CaSR activator, cinacalcet hydrochloride (hereinafter, cinacalcet), reduces not only PTH but also Ca and P in the blood by suppressing PTH secretion as when concentration of Ca<NUM>+ as the endogenous ligand is increased (Non-patent document <NUM>: <NPL>).

Administration of cinacalcet, however, is known to frequently manifest digestive symptoms such as nausea and vomiting, and thus has an issue concerning patients who have to discontinue administration or who cannot increase the dose (Non-patent document <NUM>: REGPARA (registered trademark) tablet, <NPL>), and Non-patent document <NUM>: <NPL>). While details of the mechanism involved in the digestive symptoms caused by cinacalcet are unknown, increase in the gastric acid secretion and poor peristaltic movement of the digestive tract by activation of CaSR in the digestive tract are suggested to be some of the possible causes (Non-patent document <NUM>: <NPL>).

Moreover, a CaSR agonist, etelcalcetide (N-acetyl-S-[(2R)-<NUM>-amino-<NUM>-carboxyethylsulfanyl]-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-argininamide hydrochloride), was launched under the trade name of PARSABIV (registered trademark) in <NUM> as an intravenous formulation having an efficacy and an effect for secondary hyperparathyroidism undergoing hemodialysis. Etelcalcetide, however, has problems such as excessive decrease in the serum Ca concentration, accumulating property and the like, and thus requires regular checking on patient's condition and consideration of treatments such as weight reduction and break from medication, and also requires careful medication management due to side effects such as hypersensitivity reaction and vomiting (Non-patent document <NUM>: PARSABIV (registered trademark), <NPL>, Non-patent document <NUM>: <NPL>, and Non-patent document <NUM>: <NPL>).

In this regard, <CIT> (Patent document <NUM>) and <CIT> (Patent document <NUM>) show that (<NUM>)-<NUM>-amino-<NUM>-{[(<NUM>-chloro-<NUM>-methyl-<NUM>-sulfophenyl)carbamoyl]amino}propanoic acid activates CaSR, while Patent document <NUM> shows that oral administration of the same to nephrectomized rats decreases PTH. <CIT> relates to calcium sensing receptor agonists for use in the prevention of secondary hyperparathyrodism under maintenance dialysis.

"<NPL>), relates to a dose adjustment trial of SK-<NUM>/upacicalcet/AJT-<NUM> in hemodialisys patients with secondary hyperparathyroidism.

In order to prevent or treat secondary hyperparathyroidism under maintenance dialysis, there has been a demand for a highly convenient and excellent medicinal composition.

In view of the above-described problems, the present inventors have gone through intensive investigation, and as a result of which found that <NUM>-{[(<NUM>)-<NUM>-amino-<NUM>-carboxyethyl]carbamoylamino}-<NUM>-chloro-<NUM>-methylbenzenesulfonic acid (hereinafter, Compound A), a pharmaceutically acceptable salt thereof or a solvate thereof is effective with a specific dosage and administration in preventing or treating secondary hyperparathyroidism under maintenance dialysis.

The present invention is set out in the claims and comprises, for example, the aspects described below. A compound for use in preventing or treating secondary hyperparathyroidism under maintenance dialysis, wherein the compound is <NUM>-{[(<NUM>)-<NUM>-amino-<NUM>-<NUM> carboxyethyl]carbamoylamino}-<NUM>-chloro-<NUM>-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof, and wherein the compound is intravenously administered at the end of each dialysis session in a dialysis schedule of <NUM>-<NUM> sessions a week with a daily dose for adults selected from doses of <NUM>, <NUM> or more and from doses of <NUM>, <NUM>, <NUM>, <NUM> or less, preferably <NUM>-<NUM> more preferably <NUM>-<NUM>.

A compound for use in preventing or treating secondary hyperparathyroidism under maintenance dialysis with reduced side effects, wherein the compound is <NUM>-{[(<NUM>)-<NUM>-amino-<NUM>-<NUM> carboxyethyl]carbamoylamino}-<NUM>-chloro-<NUM>-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof, and wherein the compound is intravenously administered at the end of each dialysis session in a dialysis schedule of <NUM>-<NUM> sessions a week with a daily dose for adults selected from doses of <NUM>, <NUM> or more and from doses of <NUM>, <NUM>, <NUM>, <NUM> or less, preferably <NUM>-<NUM> more preferably <NUM>-<NUM>.

A compound for use in preventing or treating secondary hyperparathyroidism under maintenance dialysis without manifesting significant accumulating property, wherein the compound is <NUM>-{[(<NUM>)-<NUM>-amino-<NUM>-<NUM> carboxyethyl] carbamoylamino}-<NUM>-chloro-<NUM>-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof, and wherein the compound is intravenously administered at the end of each dialysis session in a dialysis schedule of <NUM>-<NUM> sessions a week with a daily dose for adults selected from doses of <NUM>, <NUM> or more and from doses of <NUM>, <NUM>, <NUM>, <NUM> or less, preferably <NUM>-<NUM> more preferably <NUM>-<NUM>.

A compound for use in preventing or treating secondary hyperparathyroidism under maintenance dialysis for long term administration, wherein the compound is <NUM>-{[(<NUM>)-<NUM>-amino-<NUM>-<NUM> carboxyethyl]carbamoylamino}-<NUM>-chloro-<NUM>-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof, and wherein the compound is intravenously administered at the end of each dialysis session in a dialysis schedule of <NUM>-<NUM> sessions a week with a daily dose for adults selected from doses <NUM>, <NUM> or more and from doses of <NUM>, <NUM>, <NUM>, <NUM> or less, preferably <NUM>-<NUM> more preferably <NUM>-<NUM>.

The compound for use according to any one of the above aspects, wherein <NUM>-{[(<NUM>)-<NUM>-amino-<NUM>-carboxyethyl]carbamoylamino}-<NUM>-chloro-<NUM>-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof is sodium <NUM>-{[(<NUM>)-<NUM>-amino-<NUM>-carboxyethyl]carbamoylamino}-<NUM>-chloro-<NUM>-methylbenzenesulfonate or a solvate thereof.

The compound for use according to any one of the above aspects, wherein <NUM>-{[(<NUM>)-<NUM>-amino-<NUM>-carboxyethyl]carbamoylamino}-<NUM>-chloro-<NUM>-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof is sodium <NUM>-{[(<NUM>)-<NUM>-amino-<NUM>-carboxyethyl]carbamoylamino}-<NUM>-chloro-<NUM>-methylbenzenesulfonate.

Another aspect of the present invention comprises a compound for use in preventing or treating secondary hyperparathyroidism under maintenance dialysis, wherein the compound comprises compound A, a pharmaceutically acceptable salt thereof or a solvate thereof, and wherein the compound is intravenously administered at the end of each dialysis session in a dialysis schedule of <NUM>-<NUM> sessions a week with a daily dose for adults selected from doses of <NUM>, <NUM> or more and from doses of <NUM>, <NUM>, <NUM>, <NUM> or less, preferably <NUM>-<NUM> more preferably <NUM>-<NUM> to regulate the serum PTH concentration to the normal level.

Furthermore, another aspect of the present invention comprises a compound for use in preventing or treating secondary hyperparathyroidism under maintenance dialysis, wherein the compound comprises compound A, a pharmaceutically acceptable salt thereof or a solvate thereof, and wherein the compound is intravenously administered at the end of each dialysis session in a dialysis schedule of <NUM>-<NUM> sessions a week with a daily dose for adults selected from doses of <NUM>, <NUM> or more and from doses of <NUM>, <NUM>, <NUM>, <NUM> or less, preferably <NUM>-<NUM> preferably <NUM>-<NUM> to regulate the serum PTH and Ca concentrations to the normal levels.

The compound used in the invention may be provided in a kit comprising Compound A, a pharmaceutically acceptable salt thereof or a solvate thereof, and a label and/or an attached instruction instructing a daily dose for intravenous administration in adults at the end of dialysis ( a dose of <NUM>-<NUM>, more preferably <NUM>-<NUM>, and still more preferably <NUM>-<NUM>) for preventing or treating secondary hyperparathyroidism under maintenance dialysis.

The kit may further comprise a container for containing Compound A, a pharmaceutically acceptable salt thereof or a solvate thereof (for example, a vial, an ampoule) and/or a box (package) for packaging said container.

In the above-described kit, Compound A, a pharmaceutically acceptable salt thereof or a solvate thereof may be a medicinal composition containing Compound A, a pharmaceutically acceptable salt thereof or a solvate thereof and a pharmaceutically acceptable carrier (for example, sodium chloride, disodium hydrogen phosphate or a hydrate thereof, sodium dihydrogen phosphate or a hydrate thereof).

The present invention can provide an agent for preventing or treating secondary hyperparathyroidism under maintenance dialysis with reduced side effects or without manifesting significant accumulating property, which allows easier dosage management by medical practitioners and which is a safer drug than conventional products, and thus is beneficial for both patients and medical practitioners.

The compound for use according to the present invention can be used for a patient developing or having the risk of developing secondary hyperparathyroidism, specifically, a patient with a chronic kidney disease who is receiving dialysis on a continuous basis.

"Secondary hyperparathyroidism" refers to hyperparathyroidism that occurs from continuous presence of a factor stimulating the parathyroid glands, which is induced by abnormal bone mineral metabolism resulting from renal function disorders, and refers to a state where the serum PTH concentration prior to administration of the medicinal composition of the present invention is exceeding a certain range. A PTH concentration can be measured by various measurement methods, for example, as intact PTH (iPTH) which can be acquired by measuring only the full-length PTH, or as whole PTH which can be acquired by measuring only biologically active full-length PTH. Based on the reference values of dialysis patients which are defined for respective measurements, secondary hyperparathyroidism is diagnosed when the measured PTH values exceed a certain range. In general, secondary hyperparathyroidism is diagnosed in terms of iPTH value, specifically when iPTH exceeds <NUM> pg/ml, and in some cases when iPTH exceeds <NUM> pg/ml.

Here, in a case of hypoalbuminemia (albumin is <NUM>/dl or less), a serum Ca concentration can be corrected by the following equation.

Corrected serum Ca level [mg/dl] = Measured serum Ca level [mg/dl] + <NUM> - Serum albumin level [g/dl].

"Prevention" of secondary hyperparathyroidism means to administer the medicinal composition of the present invention to a patient whose serum PTH concentration is within the reference range of dialysis patients prior to administration of the medicinal composition of the present invention but who is at risk of developing secondary hyperparathyroidism due to renal function disorders so that the measured serum PTH concentration does not exceed the upper limit of the reference value for dialysis patients.

"Treatment" of secondary hyperparathyroidism means to administer the medicinal composition of the present invention to a patient developing secondary hyperparathyroidism so as to lower the serum PTH concentration to be lower than the concentration prior to administration of the medicinal composition of the present invention, preferably to the reference value for dialysis patients. More preferably, it means to lower the serum PTH concentration but not to fall below the lower limit value of the reference value for dialysis patients and not to exceed the upper limit value of said reference value. Moreover, at the same time as lowering the serum PTH concentration to the reference value for dialysis patients, it may also mean to suppress the progression of parathyroid hyperplasia and mineral metabolism disorders (especially, Ca and P) which are symptoms relating to secondary hyperparathyroidism, preferably to improve the symptoms from how they were before administration of the medicinal composition of the present invention, or to keep the parameters relative to the mineral metabolism disorder within the reference values for dialysis patients.

"A daily dose" of Compound A "for adults selected from doses of <NUM>, <NUM> or more and from doses of <NUM>, <NUM>, <NUM>, <NUM> or less " refers to any dose in a range of <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM> or <NUM>-<NUM>. If Compound A is a solvate, the dose refers to an amount of Compound A in terms of a nonsolvate. If Compound A is a solvate of a salt, the dose refers to an amount of free Compound A in terms of a nonsolvate. If the patient is Japanese, the dose is preferably <NUM>-<NUM>, more preferably <NUM>-<NUM>, and still more preferably <NUM>-<NUM>. The preferred given dose may vary among races. For example, the Caucasoid, Australoid and Negroid generally require a higher given dose than that preferred for the Mongoloid such as Japanese.

Since the medicinal composition of the present invention is administered at the time of dialysis (upon dialysis), if the general dialysis schedule consists of three sessions a week, the medicinal composition of the present invention is administered upon each dialysis session. In this case, assuming that the beginning of a week is Day <NUM>, dialysis is conducted, for example, on Days <NUM>, <NUM>, and <NUM>, upon which the medicinal composition of the present invention is administered, and the same schedule is repeated from next week and on. If the dialysis schedule consists of <NUM> sessions a week, or if more than <NUM> sessions are temporarily conducted due to the patient condition or the like, the medicinal composition of the present invention is administered following the same schedule of <NUM> or more dialysis sessions a week. The medicinal composition of the present invention is administered at the end of each dialysis session in the dialysis schedule of <NUM>-<NUM> sessions a week.

The phrase "the end of dialysis" means immediately before the end of dialysis, specifically, when the blood is returned immediately before the end of dialysis.

The phrase "intravenously administered" means to directly administer the drug into the vein, but, for dialysis patients, it is preferable to administer the drug from the venous side of the dialysis circuit.

More preferably, the drug is infused into the venous side of the dialysis circuit upon returning the blood at the end of dialysis.

The term "side effects" refers to side effects that have been a problem of an existing drug having the same indications, specifically, digestive symptoms such as nausea and vomiting, hypersensitivity reaction, dysgeusia, hypocalcemia, exacerbation of heart failure caused by hypocalcemia, QT prolongation, numbness, a muscle spasm, sick feeling, arrhythmia, hypotension and a spasm.

The term "reduced side effects" means that occurrence of side effects caused by an existing drug having the same indications is lower than said existing drug when administration is conducted with a specific dosage and administration according to the present invention. Specifically, it means that occurrence of said side effects is <NUM>% or less, <NUM>% or less, <NUM>% or less, <NUM>% or less, and preferably <NUM>% or less in a patient given with the medicinal composition of the present invention.

The phrase "without manifesting significant accumulating property" means that even if the medicinal composition of the present invention is continuously administered (for <NUM> month or more) with a defined dosage and administration, the concentration of Compound A in the blood is not significantly increased in proportion to the period of administration.

The phrase "used for long-term administration" means that it is a medicinal composition with fewer cases of medication discontinuation, which is more adaptable to long-term administration as compared to an existing drug having the same indications (cinacalcet, etelcalcetide). Specifically, it refers to continuous administration of <NUM> year or longer.

The phrase "regulate to the normal level" means to regulate the serum PTH or Ca concentration to a level that is judged to be clinically unproblematic by the physician, preferably, to be within the range of the reference values for dialysis patients defined for the respective inspection values. More preferably, it means that regulation to the above-mentioned level is conducted by administration within a defined dosage and administration range without any break from medication during the period of administration.

In general, the serum iPTH concentration is in a range of <NUM> pg/ml to <NUM> pg/ml, preferably in a range of <NUM> pg/ml to <NUM> pg/ml or <NUM> pg/ml to <NUM> pg/ml.

The reference serum Ca concentration of the dialysis patients (corrected serum Ca concentration in case of hypoalbuminemia) is generally in a range of <NUM>/dl to <NUM>/dl.

Note that the normal level also includes cases where there is no need of discontinuing the administration even though the concentration may temporarily deviate from the above-mentioned reference range.

The present invention comprises a medicinal composition for use according to present claim <NUM> that contains Compound A, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient and a pharmaceutically acceptable carrier such as a pharmaceutically acceptable nontoxic carrier, and also comprises a medicine consisting only of Compound A, a pharmaceutically acceptable salt thereof or a solvate thereof.

Compound A used for the present invention also comprises Compound A in a salt form. If Compound A, an active ingredient of the present invention, is in a salt form, the salt is a pharmaceutically acceptable salt or an edible salt. Examples of salts of an acidic group such as the carboxyl group in the formula include an ammonium salt, a salt with a metal such as sodium, potassium, calcium, magnesium, aluminum or zinc, a salt with an organic amine such as triethylamine, ethanolamine, morpholine, pyrrolidine, piperidine, piperazine or dicyclohexylamine, and a salt with a basic amino acid such as arginine or lysine. Examples of salts of a basic group include a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or hydrobromic acid, a salt with an organic carboxylic acid such as acetic acid, trifluoroacetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid, butyric acid, hibenzic acid, pamoic acid, enanthic acid, decanoic acid, teoclic acid, salicylic acid, lactic acid, oxalic acid, mandelic acid or malic acid, and a salt with an organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. These salts can be produced by making said compound into contact with an acid or a base that can be used for producing a pharmaceutical product.

Preferably, it is sodium salt of Compound A.

According to the present invention, Compound A or a salt thereof may be an anhydride, and may form a solvate such as a hydrate or an alcohol adduct. As used herein, "solvation" refers to a phenomenon where solute molecules or ions strongly attract the surrounding solvent molecules and form a single molecular cluster in a solution. For example, it is called hydration if the solvent is water. The solvate may be either a hydrate or a nonhydrate. A nonhydrate may use an alcohol (for example, methanol, ethanol, n-propanol), dimethylformamide or the like.

Preferably, it is a hydrate of sodium salt of Compound A.

If Compound A is obtained in a free form, it may be converted into a form of a salt, a hydrate thereof or a solvate thereof that may result from said compound, according to a conventional procedure.

Moreover, if Compound A is obtained as a salt, a hydrate or a solvate of said compound, it may be converted into a free form of Compound A, according to a conventional procedure.

Compound A is intravenously administered as a medicinal composition containing Compound A as an active ingredient. The method for applying such a medicinal composition is not particularly limited and the composition may be administered in a form of a commonly employed medicine formulation by mixing the active ingredient with a pharmaceutically acceptable nontoxic liquid carrier that is suitable for administration such as injection.

Examples of such a formulation include forms of liquid agents such as a solution, a suspension and an emulsion, and forms such as a lyophilized agent. These formulations can be prepared by a pharmaceutically common process.

Examples of the pharmaceutically acceptable nontoxic carrier include water and physiological saline. In addition, if necessary, a common additive such as a pH control agent, a stabilizer, an emulsifier or a tonicity agent may also suitably be added.

The medicinal composition of the present invention can be formulated by a conventional procedure. In accordance with the pharmaceutical need, various pharmacologically acceptable substances for formulation may be added (as adjuvants or the like). The substance for formulation may appropriately be selected in accordance with the dosage form of the formulation. For example, if the formulation is a solution, examples of the substance for formulation include sterilized water and a monohydric or polyhydric alcohol such as glycerol.

The medicinal composition of the present invention may include an insert instructing the use thereof inside the package. An example of such an insert includes so-called instructions explaining the usage, efficacy, administration method and the like.

In accordance with symptoms of the patient, the medicinal composition of the present invention may be used in combination with a calcium agent or a vitamin D formulation. The dosage and administration of the calcium agent or the vitamin D formulation used in combination can appropriately be determined according to the blood Ca concentration.

Hereinafter, the present invention will be described specifically by means of examples, although the present invention should not be interpreted to be limited to these examples.

To <NUM> (<NUM> mmol) of <NUM>-amino-<NUM>-chloro-<NUM>-methylbenzenesulfonic acid (ACTS), <NUM> (<NUM>/kg vs ACTS) of acetonitrile, <NUM> (<NUM> mmol, <NUM> eq. ) of pyridine were added and stirred at <NUM>. <NUM> (<NUM> mmol, <NUM> eq. ) of ClCO<NUM>Ph was dropped into the resultant, which was stirred for <NUM> minutes and thereafter the end of carbamate reaction was confirmed by HPLC. <NUM> (<NUM> mmol, <NUM> eq. ) of <NUM>-amino-N-(tert-butoxycarbonyl)-L-alanine methyl ester hydrochloride was added and <NUM> (<NUM> mmol, <NUM> eq. ) of triethylamine was dropped into the resultant, which was stirred at <NUM> for <NUM> hours. <NUM> (<NUM> mmol, <NUM> eq. ) of <NUM>-amino-N-(tert-butoxycarbonyl)-L-alanine methyl ester hydrochloride and <NUM> (<NUM> mmol, <NUM> eq. ) of triethylamine were further added, and the end of urea-forming reaction was confirmed by HPLC. <NUM> (<NUM> mmol, <NUM> eq. ) of methanesulfonic acid was added, and the resultant was heated to <NUM> and stirred for <NUM> hours. After confirming the end of deprotection by HPLC, the resultant was cooled to <NUM> and added with <NUM> (<NUM>/kg) of acetonitrile and <NUM> (<NUM>/kg) of water to allow deposition of a solid. The resultant was cooled to <NUM> and matured for <NUM> hours. The deposited solid was filtrated under reduced pressure, washed with <NUM> (<NUM>/kg) of water/acetonitrile (<NUM>/<NUM>), and then dried under reduced pressure at <NUM> for <NUM> hours to give <NUM> of the compound of interest as a white solid (net <NUM>, <NUM>%).

<NUM>H-NMR (<NUM>, DMSO-d6): δ <NUM> (bs, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (t, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

HRMS (FAB-): calcd for m/z <NUM> (M-H), found m/z <NUM> (M-H).

To <NUM> (net <NUM>, <NUM> mmol) of the compound obtained in Step <NUM>, <NUM> (<NUM>/kg vs compound of Step <NUM>) of water was added and the resultant was stirred at <NUM>. <NUM> (<NUM> mmol, <NUM> eq. ) of a <NUM>% aqueous sodium hydroxide solution was dropped into the resultant, which was washed with <NUM> (<NUM>/kg) of water and then stirred at <NUM> for <NUM> minutes. After confirming the end of hydrolysis by HPLC, the resultant was heated to <NUM>, to which about <NUM> of <NUM>% HBr aq. was added to control pH to <NUM>. <NUM> (<NUM>/kg) of isopropyl alcohol was dropped into the resultant. After confirming deposition of the compound of interest, the resultant was matured for an hour. <NUM> (<NUM>/kg) of isopropyl alcohol was dropped into the resultant and matured at <NUM> overnight. The deposited solid was filtrated under reduced pressure, washed with <NUM> (<NUM>/kg) of isopropyl alcohol, and dried under reduced pressure at <NUM> for <NUM> hours to give <NUM> of the compound of interest as a white solid (net <NUM>, <NUM>%).

<NUM>H-NMR (<NUM>, DMSO-d6): δ <NUM> (s, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM>-<NUM> (bs, <NUM>), <NUM> (d, <NUM>, J=<NUM>), <NUM> (t, <NUM>, J=<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

After quarantine and acclimatization periods of <NUM> days, fifty-one <NUM>-week-old rats (Crl: CD (SD), male) were fed a <NUM>% sucrose diet ad libitum from four days before the surgery. On the day of the surgery, skin incisions were made on the back at the sites of the right and left kidneys under isoflurane anesthesia and the renal capsules were removed to ligate the renal arteries and veins and the ureters using threads before removing the right and left kidneys. A penicillin solution was given upon suturing, and <NUM> of physiological saline was intraperitoneally administered before returning the rats into the breeding cages.

On the day of administering the test substance, i.e., a day after the bilaterally nephrectomy, approximately <NUM>µL of blood was collected from the tail vein without anesthesia using a capillary tube, which was centrifuged in a high speed refrigerated microcentrifuge (<NUM> rpm, <NUM>, <NUM>) to separate the serum. Thereafter, the serum Ca concentration was measured with a dri-chem analyzer (model number: FUJI DRI-CHEM <NUM>, manufacturer: FUJIFILM Medical Co. ) to select individuals with a serum Ca concentration of <NUM>/dL or more and less than <NUM>/dL.

On a day after the bilaterally nephrectomy, the given doses were calculated based on the weight of the selected animals on that day. Group <NUM> was given a medium (physiological saline), Groups <NUM>, <NUM> and <NUM> were given the Compound A1 solution (<NUM>, <NUM> and <NUM>/mL, respectively), and Groups <NUM>, <NUM>, <NUM> and <NUM> (<NUM> rats per group) were given the comparative compound (<NUM>, <NUM>, <NUM> and <NUM>/mL, respectively), each given a single dose of <NUM>/kg from the tail vein. Prior to the administration (<NUM> hour), and <NUM> and <NUM> hours after the administration, approximately <NUM>µL of blood was collected without anesthesia from the tail vein using capillary tubes for obtaining the serum. The blood for obtaining the serum was left to stand at room temperature, and centrifuged in a high speed refrigerated microcentrifuge (<NUM> rpm, <NUM>, <NUM>) within a period of <NUM> minutes to <NUM> hours after the blood collection to collect the serum.

Thereafter, the serum Ca was analyzed with COBAS analyzer (Model number: COBAS INTEGRA <NUM> plus, manufacturer: Roche Diagnostics K. ), and the remaining serum was stored in an ultra-low freezer (temperature set to -<NUM> ± <NUM>) until the day of iPTH measurement. On the day of iPTH measurement, the serum was melted at room temperature for measurement.

A <NUM>/ml Compound A1 solution (<NUM> of Compound A1 dissolved in <NUM> of physiological saline) was diluted with physiological saline to prepare <NUM>/ml and <NUM>/ml Compound A1 solutions.

<NUM> of etelcalcetide (Ac-c(C) arrrar-NH<NUM>) TFA salt (<CIT>) was prepared to have pH of <NUM>-<NUM> with <NUM> of physiological saline and a <NUM>. 5N aqueous NaOH solution, to which physiological saline was further added to make <NUM>. The prepared <NUM>/ml comparative compound solution was diluted with physiological saline to give <NUM>/ml and <NUM>/ml comparative compound solutions.

The mean ± standard error of the serum iPTH concentrations of all individuals prior to the administration (<NUM> hour) was <NUM> ± <NUM> pg/ml. Administrations of Compound A1 at <NUM>, <NUM> and <NUM>/kg decreased the serum iPTH concentrations, where the means were <NUM>, <NUM> and <NUM>/dL <NUM> hours after the administration, respectively, and <NUM>, <NUM> and <NUM>/dL <NUM> hours after the administration, respectively. Here, the plasma Compound A1 concentration <NUM> hours after a single intravenous dose of Compound A1 at <NUM>/kg in the bilaterally nephrectomized rats was estimated to be <NUM>µg/ml, maintaining sufficiently higher concentration than the <NUM>% effective concentration, i.e., EC<NUM> value, of <NUM> ng/ml for decreasing the serum iPTH concentration.

Meanwhile, administrations of the comparative compound at <NUM>, <NUM>, <NUM> and <NUM>/kg also decreased the serum iPTH concentration, where the mean serum iPTH concentrations were <NUM>, <NUM>, <NUM> and <NUM>/dL <NUM> hours after the administration, respectively, and <NUM>, <NUM>, <NUM> and <NUM> (n = <NUM>) mg/dL <NUM> hours after the administration, respectively. Here, the concentration of the comparative compound in the plasma <NUM> hours after a single intravenous dose of the comparative compound at <NUM>/kg in the bilaterally nephrectomized rats was estimated to be <NUM>µg/ml, maintaining sufficiently higher concentration than the <NUM>% effective concentration, i.e., EC<NUM> value, of <NUM> ng/ml for decreasing the serum iPTH concentration. Logistic curve fitting was conducted to establish the response relationship between the serum iPTH concentration <NUM> hours after the administration and the given dose. As a result, the lower limit values of the serum iPTH concentrations by administrations of Compound A1 and the comparative compound were simulated to be <NUM> pg/ml and <NUM> pg/ml, respectively (<FIG>).

The mean ± standard error of the serum Ca concentration of all individuals prior to the administration (<NUM> hour) was <NUM> ± <NUM>/dL.

Administrations of Compound A1 at <NUM>, <NUM> and <NUM>/kg decreased the serum Ca concentrations, where the means were <NUM>, <NUM> and <NUM>/dL <NUM> hours after the administration, respectively, and <NUM>, <NUM> and <NUM>/dL <NUM> hours after the administration, respectively.

Meanwhile, administrations of the comparative compound at <NUM>, <NUM>, <NUM> and <NUM>/kg also decreased the serum Ca concentration, where the mean serum Ca concentrations were <NUM>, <NUM>, <NUM> and <NUM>/dL <NUM> hours after the administration, respectively, and <NUM>, <NUM>, <NUM> and <NUM> (n = <NUM>) mg/dL <NUM> hours after the administration, respectively.

Logistic curve fitting was conducted to establish the response relationship between the serum Ca concentration <NUM> hours after the administration and the given dose. As a result, the lower limit values of the serum Ca concentrations by administrations of Compound A1 and the comparative compound were simulated to be <NUM>/dL and <NUM>/dL, respectively (<FIG>).

The number of rats in each group was five prior to the administration. While all five rats survived <NUM> hours after the administration in the medium-administered group and the Compound A1-administered groups, four survived in the <NUM>/kg group and one survived in the <NUM>/kg group among the comparative compound-administered groups (<FIG>).

Compound A1 is a CaSR activator used for intravenous administration. Non-clinical studies show that renal excretion is the main route of excretion, and when the compound is intravenously administered to a normal rat, the compound is rapidly eliminated from the plasma. In renal failure rat models, serum iPTH and Ca concentrations sufficiently decreased during the <NUM> hours after the administration but the decreases were gradual with respect to the increase in the dose.

On the other hand, already launched etelcalcetide having the same action mechanism decreased the serum iPTH and Ca concentrations in a dose-dependent manner, but the number of dead rats increased in a dose-dependent manner.

These results show that Compound A1, as compared to etelcalcetide, had advantageous effect of not decreasing the serum iPTH and Ca concentrations to an extent affecting maintenance of life, and that it was useful for controlling the serum iPTH and Ca concentrations in nephropathy patients.

A crossover trial was conducted with male beagles (Nosan Beagle, <NUM>-<NUM>-month-old, weight: <NUM>-<NUM>). The Compound A1 solutions used in Example <NUM> were given at <NUM>, <NUM> and <NUM>/kg by bolus administration (<NUM>/kg, <NUM>/sec) to <NUM>-<NUM> dogs per dose to confirm the manifestation of vomiting immediately after the administration. Administration was conducted once or twice a week with a <NUM>-day interval. Administration was conducted prior to feeding.

For administration at <NUM>/kg with no vomiting case in the dogs, C<NUM> was <NUM>. Assuming that an effective dose in human was <NUM>/man in view of Example <NUM> below, C<NUM> was <NUM> based on the analysis results acquired by simultaneously fitting all doses.

From the above results, Compound A1 was found to have a <NUM> times or more higher therapeutic margin in human than in dogs with respect to vomiting.

Cinacalcet is known to frequently manifest digestive symptoms such as nausea and vomiting, which are factors that inhibit continuous administration. On the other hand, since the dose of Compound A1 of the present invention given to human greatly differs from the dose that manifests vomiting in dogs, it appears to be a medicinal composition that has few side effect such as vomiting in human, that is safe and that is adaptable to long-term administration.

SD male rats (<NUM>-week-old) were used to isolate rat peritoneal mast cells according to the method of Kimura et al. Compound A1 was added to these mast cells to determine the amount of released histamine according to the method of Liu J et al. (<NPL>) to compare the effects of Compound A1, the comparative compound, and Compound <NUM>/<NUM> as positive control on histamine release. Specifically, the test substance was added to the peritoneal cell suspension obtained from SD rats ( cell concentration of <NUM> × <NUM><NUM> cells/ml), and determined the histamine concentration in the cell supernatant after incubated at <NUM> for <NUM> minutes. Here, etelcalcetide was used as the comparative compound; Compound A1 and the comparative compound were each prepared into five groups of <NUM>-<NUM> in the same manner as Example <NUM>; and Compound <NUM>/<NUM> (manufactured by Sigma) was tested at concentrations of <NUM>/ml and <NUM>/ml.

The inhibition ratio was calculated by the following equation.

As can be appreciated from <FIG>, Compound A1 was shown to induce almost no histamine release. Meanwhile, the comparative compound increased the released histamine level in a dose-dependent manner.

Etelcalcetide is known to have the risk of developing hypersensitivity reaction, and thus requires great caution upon administration. On the other hand, since Compound A1 of the present invention hardly causes histamine release which is a major cause of hypersensitivity reaction, it has a low probability of developing hypersensitivity reaction and thus was confirmed to be a medicinal composition with reduced side effects.

Thirty-two healthy Japanese male adults were given a single intravenous dose of the test drug (Compound A1) at <NUM>, <NUM>, <NUM> or <NUM> in a fasted state to study the pharmacokinetics, pharmacodynamics and safety by a double-blind test using a placebo as a control. Here, the trial drug was administered by diluting a required dose taken from the Compound A1 vial formulation prepared as follows with sterilized water for injection, and filling a syringe with the resultant in accordance with the dose to be administered.

A vial formulation encapsulating <NUM> of Compound A1 in terms of a dehydrate, and sodium chloride, disodium hydrogen phosphate dodecahydrate and sodium dihydrogen phosphate dihydrate as additives in <NUM> of sterilized water for injection.

A vial formulation encapsulating <NUM> of sterilized water for injection without Compound A1.

In the phase I trial that targeted healthy male adults and that used a placebo as a control, single intravenous doses of <NUM>, <NUM>, <NUM> and <NUM> Compound A1 were present as generally unchanged substances in the plasma and rapidly eliminated. Furthermore, since they were excreted into the urine mostly as unchanged substances with respect to the given dose, renal excretion was found to be the main elimination pathway of the unchanged substance. In the pharmacodynamic evaluations, the serum iPTH concentration was confirmed to have decreased in the <NUM> and higher dose groups as compared to that before the administration, where the duration of decreased serum iPTH concentration extended with the increase in the given dose. As to safety, non-severe and mild side effects such as vomiting were observed in the <NUM> and higher dose groups, but no other problematic event was observed.

A PK/PD analysis was conducted to estimate the clinically effective dose based on the results from P1. The dose of <NUM> seemed to be excessive and thus was eliminated from the analysis. PK (mean plasma concentration) and PD (mean iPTH level normalized by the levels of the placebo group and the <NUM>-hour level) data of the doses of <NUM>, <NUM> and <NUM> were used. An indirect response model incorporating rebound was used for the PK/PD analysis.

Based on the results of PK of the three given doses (<NUM>, <NUM> and <NUM>) in P1, the three given doses were simultaneously analyzed using a three-compartment model to calculate the PK parameters (<FIG> and Table <NUM>).

Using the calculated PK parameters as an input function, PK/PD analysis was performed using an indirect response model incorporating rebound (<FIG>) to calculate the EC<NUM> value in healthy adults (<FIG> and Table <NUM>).

EC<NUM> value in patient with renal failure was estimated based on the calculated EC<NUM> value in healthy adults and the results from the same analysis in normal rats and adenine-treated rat models (pathological rat models). First, EC<NUM> values were calculated in the same manner in rats, which were < <NUM> ng/mL in normal rats and <NUM> ng/mL in adenine-treated rat models. Since the difference in the EC<NUM> value between rats in normal state and pathological state is presumed to be caused by the changes in PK that are considered to greatly vary between normal state and pathological state, similar tendency is expected in human as well. Accordingly, the scaling factor of EC<NUM> values of the heathy individuals and the patients with renal failure was set to "> <NUM>". This scaling factor was applied to human, whereby EC<NUM> value was estimated to be ><NUM> ng/ml in the patients with renal failure.

The result from PK fitting, and the contribution rate of renal elimination of the drug (<NUM>%) calculated using PK-sim (registered trademark) were used to simulate PK prediction in the patients with renal failure. This simulation for PK prediction and the previously estimated EC<NUM> value in the patients with renal failure (> <NUM> ng/mL) were used to estimate a given dose that allows the plasma concentration of the drug to maintain the EC<NUM> value for <NUM> hours in the patients with renal failure, which was assumed to be the estimated clinically effective dose. As a result, administration of a dose of <NUM>/man was estimated to maintain a concentration higher than <NUM> ng/ml for <NUM> hours (<FIG>). The clinically effective dose was estimated to be <NUM>/man considering that its EC<NUM> value exceeds <NUM> ng/ml.

Targeting SHPT patients on maintenance hemodialysis, pharmacokinetics, pharmacodynamics and safety upon single or repeated intravenous administration of Compound A1 were examined by conducting a double-blind test using a placebo as a control.

Single administration: Based on the clinically effective dose calculated in Example <NUM>, the doses were given at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> (<NUM> steps). On the day of trial drug administration, the trial drug was intravenously administered as slow as possible within <NUM> seconds <NUM> to <NUM> hours following the end of dialysis. Here, the trial drug was administered by diluting a required dose taken from the Compound A1 vial formulation prepared as follows with sterilized water for injection, and filling a syringe with the resultant in accordance with the dose to be administered.

Repeated administration: Based on the clinically effective dose calculated in Example <NUM>, the doses were given in <NUM> steps, namely, <NUM>, <NUM> and <NUM>. The trial drug was (intravenously) infused from the venous side of the dialysis circuit before the end of dialysis three times a week for <NUM> days (total of <NUM> times) starting from the first day of administration of the trial drug. Here, the trial drug was administered by diluting a required dose taken from the Compound A1 vial formulation prepared as follows with sterilized water for injection, and filling a syringe with the resultant in accordance with the dose to be administered.

Each item was evaluated according to the predetermined evaluation schedule.

Pharmacokinetic evaluation: Cmax and AUC of Compound A1 in plasma increased with the increase in the given dose. t1/<NUM> was <NUM>-<NUM> hours. When hemodialysis was performed <NUM> hours after the administration, the plasma Compound A1 concentration became lower immediately after the dialysis by <NUM>-<NUM>% than that just before the dialysis.

Serum iPTH concentration: In the Compound A1-administered group, the serum iPTH concentration became lower than that just before the administration with a single administration, where the effect continued up to <NUM> hours after the administration (just before the dialysis). Here, the change in the serum iPTH concentration <NUM> hours after the administration was a percentage decrease of <NUM>% in the <NUM> dose group, <NUM>% in the <NUM> dose group, <NUM>% in the <NUM> dose group, <NUM>% in the <NUM> dose group, <NUM>% in the <NUM> dose group, <NUM>% in the <NUM> dose group, and <NUM>% in the <NUM> dose group.

Safety: While relative vomiting and nausea were observed upon a single administration in the <NUM> and higher dose groups and in the <NUM> and higher dose groups, respectively, both were non-severe and mild events and no other clinical problem was observed.

Pharmacokinetic evaluation: Compound A1 was present mainly as an unchanged substance in the plasma with repeated administration. Furthermore, since the trough concentration of Compound A1 was generally constant before the dialysis following the longest interval between the dialysis sessions, the trough concentration of Compound A1 in the plasma was found not to rise before the dialysis by the repeated administration. Thus, the medicinal composition of the present invention was found to be rapidly eliminated by dialysis and has not no accumulating property.

Serum iPTH concentration: In the Compound A1-administered group, the serum iPTH concentration decreased during the test period and thus Compound A1 maintained its effect with repeated administration. Here, the change in the serum iPTH concentration on Day <NUM> of the test (three days after the ninth Compound A1 administration) was a percentage decrease of <NUM>% in the <NUM> dose group, <NUM>% in the <NUM> dose group, and <NUM>% in the <NUM> dose group.

Safety: Although decrease in the corrected Ca was observed in the <NUM> dose group and the <NUM> dose group with repeated administration, all of them were mild and none caused a problem significant to safety. Decrease in the corrected Ca was not observed in the <NUM> dose group.

From the above results, the medicinal composition of the present invention was found to be useful as an agent for preventing or treating secondary hyperparathyroidism with reduced side effects when used in Japanese adults with a daily dose in a range of <NUM>-<NUM>.

Claim 1:
A compound for use in preventing or treating secondary hyperparathyroidism under maintenance dialysis, wherein the compound is <NUM>-{[(<NUM>)-<NUM>-amino-<NUM>-carboxyethyl]carbamoylamino}-<NUM>-chloro-<NUM>-methylbenzenesulfonic acid, a pharmaceutically acceptable salt thereof or a solvate thereof, and wherein the compound is intravenously administered at the end of each dialysis session in a dialysis schedule of <NUM>-<NUM> sessions a week with a daily dose of <NUM>-<NUM> for adults.