EP1515728A2

EP1515728A2 - Use of orally-available prostacyclin derivatives for the production of a medicament for the treatment of disease states associated with bone marrow oedema

Info

Publication number: EP1515728A2
Application number: EP03735573A
Authority: EP
Inventors: Cornelia Norden; Nicolas Aigner
Original assignee: Schering AG
Current assignee: Bayer Pharma AG
Priority date: 2002-06-06
Filing date: 2003-06-05
Publication date: 2005-03-23
Also published as: DE10225551A1; AU2003236715A1; WO2003103681A3; KR20050007591A; JP2005536476A; CN1658882A; ZA200500097B; CA2488861A1; WO2003103681A2

Abstract

The invention relates to the use of orally-available prostacyclin derivatives for the production of a medicament for the treatment of disease states associated with bone marrow oedema.

Description

Use of orally available prostacyclin derivatives for the

Manufacture of a medicinal product for the treatment of diseases associated with

Bone marrow edema is associated

The invention relates to the subject-matter set out in the patent claims, that is to say the use of orally available prostacyclin derivatives for the production of a medicament for the treatment of diseases which are associated with bone marrow edema.

For osteonecrosis and, more recently, for osteoarthritis in the knee, a connection between the presence of bone marrow edema and pain is assumed (Felson et al., Ann Intern Med, 2001, 134 (7): 541- 593).

Osteonecrosis (syn .: aseptic necrosis, avascular necrosis, ischemic necrosis) is a common disease. Pain is the main symptom. In about two thirds of the patients, this pain occurs at rest. Osteonecrosis is often described as a transient process. In the spontaneous course, there is usually a complete healing after 6 to 12 months. During this period, however, the patient is exposed to severe pain, which is often not even accessible to conventional pain therapy. The incidence rates of the progression of early osteonecrosis to the end stage with pronounced bone necrosis are not known. Osteonecrosis is responsible for more than 10% of all joint replacement surgery performed annually.

Knee osteoarthritis is a common disease that affects approximately 11-15% of people over 65 and is the most common cause of physical illness

Disability of the elderly. The main reason for physical impairment and visits to the doctor is knee pain. Osteoarthritis is defined as primarily non-inflammatory joint destruction, which begins with cartilage dying in adults and later also affects the other joint structures and progresses irreversibly. The overall course is usually progressive, but changes in phases with regard to clinical acuity. In the final stage, knee replacement is necessary.

The most common manifestations are osteonecrosis and osteoarthritis on the hip and knee joints, but also on the shoulder, wrist and ankle. While in the treatment of osteonecrosis the surgical

Bone marrow relief (drilling) with all its disadvantages such as inpatient stay and surgery as a means of pain relief, the treatment of osteoarthritis currently consists only of symptomatic pain treatment and is insufficiently effective. It usually includes the permanent prescription of analgesics and / or anti-inflammatory drugs, combined with physiotherapy and weight relief, and possibly the intra-articular injection of anesthetics, corticoids or "cartilage building / replacing" substances. X-ray stimulation and acupuncture are also prescribed. The treatment of arthrosis has so far been limited to symptomatic treatment.

The established therapies are unsatisfactory for both osteonecrosis and osteoarthritis due to the limitation to symptomatic treatment. In particular, the persistence of the pain-triggering mechanisms requires long-term treatment, which is associated with additional risks and costs. A causal treatment of the pain with permanent freedom from pain is therefore particularly desirable for osteoarthritis.

It is known that pain relief can be achieved with osteonecrosis by a five-day intravenous infusion therapy with llomedin ^® (iloprost trometamol) (Aigner et al, J Bone Joint Surg, 2001, 83 (6):. 855-858). However, the short-term freedom from pain with a decrease in bone marrow edema does not relieve the doctor from close monitoring over a longer period of time, since the freedom from pain which is masked a possible progression to a necrotic stage of the bone. Therefore, beyond the freedom from pain, the treatment of necrotic lesions is the goal the maintenance or restoration of healthy bone tissue is desirable.

The object was therefore to find a treatment for the diseases associated with bone marrow edema, in particular osteonecrosis and osteoarthritis, which did not only relate to the symptomatic treatment, i.e. pain relief, but also restores the structural integrity of the bone, and also to provide a drug that can be taken by the patient over a long period of time without the doctor's support.

It has now surprisingly been found to be orally available

Prostacyclin derivatives, especially the cyclodextrin clathrates of prostacyclin derivatives of the general formula I

(I)

wherein R ^{1 is} a hydrogen atom or a Ci-C-io-alkyl radical,

A is a -CH ₂ -CH ₂ - group, a trans -CH = CH- group or one

-C≡C- group

W is a free or functionally modified on the hydroxy group

Hydroxymethylene group, the hydroxyl group being α or β,

X, Y independently of one another are a -CH ₂ group or an oxygen atom,

Z is a hydrogen atom or a cyano group,

D is a straight-chain or branched saturated -CC ₅ alkylene group

E is a -C≡C group or a direct bond, R ^{2 is} a straight-chain or branched, saturated C 1 -C ₇ -alkyl group R ^{3 is} a free or functionally modified hydroxyl group, and all optically active forms, racemates, diastereomers, mixtures of diastereomers, their clathrates, and if R is hydrogen, their salts with physiologically compatible bases solve the task.

A 28-day treatment of patients with painful bone marrow edema with lloprost ß-cyclodextrin clathrate (lloprost oral) not only reduced the bone marrow edema but also restored the structural integrity, i.e. necrotic areas and lesions were healed. Pain relief and improved joint function were observed even 2 months after the end of treatment. Treatment with orally available prostacyclin derivatives, in particular with cyclodextrin clathrates of prostacyclin derivatives of formula I, is a novel therapy that not only suppresses the symptoms, i.e. the pain, but also combats the cause of osteonecrosis and osteoarthritis, and for the first time also clinic can be done independently.

This finding is all the more surprising since earlier studies such as the placebo-controlled studies for the treatment of severe leg ischemia have shown no efficacy of lloprost ß-cyclodextrin clathrate (Eur J Vase Endovasc Surg., 2000, 20 (4): 358-362). Thus, the efficacy of intravenous treatment with iloprost trometamol, which is approved for the treatment of severe leg ischemia, could not be reproduced. An advantageous effectiveness of lloprost ß-cyclodextrin clathrate is therefore not predictable in every case based on knowledge of intravenous iloprost trometamol.

The alkyl group R ¹ is straight-chain or branched alkyl groups with 1-10 carbon atoms, such as methyl, ethyl, propyl, 2-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl (tert.- Butyl), hexyl, heptyl, octyl, nonyl, decyl. The alkyl group R ¹ can also be substituted. Examples of substituents are fluorine, chlorine or bromine atoms, phenyl, dimethylamino, diethylamino, methoxy, ethoxy.

Alkyl groups with 1-4 carbon atoms are preferred as the alkyl group R ¹ .

The alkyl group R ² is straight-chain or branched, reference may be made, for example, to the radicals of corresponding chain length mentioned for R ¹ , and has 1-7 carbon atoms, preferably 1-3 carbon atoms, particularly preferably 1-2.

The hydroxyl groups in R ³ and W can be functionally modified. This means esterification or etherification. The ethers and / or acyl radicals thus obtained are the radicals known to the person skilled in the art.

Ether residues are e.g. Tetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, methoxyethyl, ethoxyethyl, silyl ether such as e.g. Trimethylsilyl, dimethyl tert-butylsilyl, triphenylsilyl. Acyl radicals can be, for example, acetyl, propionyl, butyryl, benzoyl.

X preferably has the meaning of a CH ₂ group.

Z preferably represents a hydrogen atom.

As the alkylene group D straight-chain or branched saturated alkylene group with 1-5 carbon atoms are suitable. Examples include methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 2-methylpropylene, pentylene, 1-methylbutylene and ethylethylene. A branched alkylene group having 3 carbon atoms is preferred.

If R ^{1 represents} a hydrogen atom, the compounds of the formula I can also be present as salts of physiologically compatible bases. Both inorganic and organic bases are suitable for salt formation. For example, alkali hydroxides such as sodium or

Potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine. The prostacyclin derivatives are orally available in the sense according to the invention when they can be used for oral administration after a suitable formulation.

In addition, their α- or β-cyclodextrin clathrates or their hydroxylated forms are particularly suitable.

Particularly suitable for the treatment of diseases associated with bone marrow edema, in particular for the treatment of osteonecrosis and osteoarthritis, are also the following known prostacyclin derivatives of the general formula I formulated for oral administration: cicaprost (5 - {(E) - ( 1 S, 5S, 6S, 7R) -7-hydroxy-6 - [(3S, 4S) -3-hydroxy-4-methyl-1, 6-nonadiynyl] bicyclo [3.3.0] oct-3-ylidene } -3-oxapentanoic acid), epoprostenol ((5Z, 9, 13E, 15S) -6,9-epoxy-11,15-dihydroxy-prosta-5,13-diene-1-acid), beraprost (EP 0 084856) , Ciprostene, Taprostene, Naxaprostene, CS 570, SC-39902, FCE-22509, OP 41483 and RS 93427.

The β-cyclodextrin clathrate from lloprost, (5-

{(1S, 5S, 6R, 7R) -7-hydroxy-6 - [(E) - (3R, 4RS) -3-hydroxy-4-methyl-oct-1-en-6-ynyl] - bicyclo [3.3 .0] octan-3-ylidene} -pentanoic acid) -beta-cyclodextrin clathrate. Within a 28-day treatment, there is a significant, quickly noticeable improvement in pain, which is associated with a significant decrease in bone marrow edema and healing of necrosis.

Therefore, the use of hoprost-β-cyclodextrin clathrate for the manufacture of a medicament for the treatment of osteonecrosis and osteoarthritis is a preferred subject of the invention.

lloprost is a prostacyclin analogue which is known from EP 11 591 and can be produced by the methods disclosed therein. The nomenclature name for lloprost is (5 - {(1 S, 5S, 6R, 7R) -7-hydroxy-6 - [(E) - (3R, 4RS) -3-hydro) (y-4-methyl-oct- 1-en-6-ynyl] -bicyclo [3.3.0] octan-3-ylidene} -pentanoic acid).

lloprost-β-cyclodextrin clathrate, that is known from EP 259468 and can be produced by the method disclosed therein. It is known from EP 1 016 408 that prostanoϊde CC chemokine production are inhibitors. According to current knowledge, the mechanisms disclosed there are not relevant for bone marrow edema.

With regard to conventional methods for the treatment of osteonecrosis and osteoarthritis, avoiding an expensive inpatient stay, saving on surgical interventions (drilling, especially for osteonecrosis), reducing the need for implantation of artificial joints, avoiding costs for treating side effects of the conventional pain medication, reducing the Sick leave, shortening the period of incapacity to work, improving the quality of life and reducing the number of visits to the doctor are noteworthy advantages. Oral administration in particular enables long-term medication with a causal therapy approach that is pleasant for the patient and largely independent of medical support.

The appropriate dose range for the treatment of osteonecrosis and

Osteoarthritis is between 50 μg / day and 350 μg / day, preferably between 100 μg / day and 300 μg / day or between 150 μg / day and 350 μg / day, these amounts being able to be divided into several individual doses. Healing of the bone necrosis can be achieved within a few weeks.

Description of the figures

Figure 1: Significant decrease in pain at rest under oral lloprost treatment measured using a 100 mm visual analog scale with the end points 0 = no pain and 100 = unbearable pain. The pain relief is clear after only 3 days of treatment. Almost complete freedom from pain is achieved after 28 days of treatment and continues over a 2-month therapy-free period.

Data as mean values ± SEM. p-values as a comparison of the corresponding point in time with the initial value, with * p <0.05 and ^** p <0.001 (ANOVA) Figure 2: Significant decrease in pain after defined exposure measured using a 100 mm visual analog scale with the end points 0 = no pain and 100 = unbearable pain. The pain relief is clear after only 3 days of treatment. Almost complete freedom from pain is achieved after 28 days of treatment and continues over a 2-month therapy-free period.

Data as mean values ± SEM. p-values as a comparison of the corresponding point in time with the initial value, with * p <0.05 and ^** p <0.001 (ANOVA)

Figure 3: Significant increase in Larson knee activity score

(Maximum point 100) after 14 days of treatment. The improvement continues over a 2-month therapy-free period.

Data as mean values + SEM. p-values as a comparison of the corresponding point in time with the initial value, with * p <0.05 and ** p <0.001 (ANOVA)

Figure 4: Case study of a patient with complete regression of an extensive bone marrow edema in the early stage of osteonecrosis. The control MRI was performed 2 months after the 28 day treatment with oral lloprost was completed.

Figure 5: Equally pronounced decrease in pain at rest with double-blind administration of oral lloprost treatment and Tramadol ^® treatment measured using a 100 mm visual analog scale with the end points 0 = no pain and 100 = unbearable pain. Almost complete freedom from pain is achieved after 28 days of treatment and continues over a 2-month therapy-free period.

Data as mean values ± SEM. p-values for comparison of the two treatments prove their equivalence (Hodges-Lehmann estimator and Wilcoxon test). Figure 6: Equally pronounced decrease in stress pain with double-blind administration of oral lloprost treatment and Tramadol ^® treatment measured using a 100 mm visual analog scale with the end points 0 = no pain and 100 = unbearable pain. A significant reduction in pain is achieved after 28 days of treatment and continues over a 2-month therapy-free period. Data as mean values ± SEM. p-values for comparison of the two treatments prove their equivalence (Hodges-Lehmann estimator and Wilcoxon test).

Figure 7: Equally pronounced increase in knee activity score according to Larson (point maximum 100) with double-blind administration of oral lloprost treatment and Tramadol ^® treatment. The improvement continues over a 2-month therapy-free period. Data as mean values + SEM. p-values to compare the two

Treatments prove their equivalence (Hodges-Lehmann estimator and Wilcoxon test).

Figure 8: Oral lloprost caused complete regression of the bone marrow edema in at least one affected bone in 53% of the patients, whereas this was only the case in 19% of the patients taking Tramadol ^® . This difference was statistically significant (p = 0.0336, Fisher's exact test)

Experimental part

pilot study

An open pilot study was conducted in 19 patients with osteonecrosis of the knee in the 1st orthopedic department of the Orthopedic Hospital Vienna-Speising, Prim. Dr. on the effect of oral lloprost on bone marrow edema and pain. F. Landsiedl / Dr. N. Aigner, carried out from March to November 2001.

All patients gave their prior written consent to participate in the study after being informed verbally and in writing about the nature, aim and course of the study.

Patients of both sexes with rest pain due to osteonecrosis were included in the study if the following criteria were met:

• age between 19 and 60 years,

• Bone marrow edema diagnosed by MRI according to specified criteria. • Normal X-ray findings without signs of osteoarthritis and no subchondral involvement of the bone.

The treatment was carried out with Iloprost capsules, which were packed and labeled in accordance with the applicable GLP rules. Each capsule contained 50 μg lloprost. During the first three days of treatment, lloprost was administered in a dose of 3x50 μg lloprost per day, which could be increased individually from day 4 up to a maximum dose of 3x100 μg lloprost per day:

, To increase the success of the therapy (pain relief), this dosage could be achieved either by increasing the single dose (maximum: 3x100 μg lloprost per day) or by shortening the free interval (minimum: 2 h, i.e. 6x50 μg lloprost per day).

, In the event of poor tolerance, the dosage could be reduced at any time up to a minimum dose of 2x50 μg lloprost a day. The duration of treatment was one month. Pain-relieving drugs previously administered should be discontinued before the start of the study.

All medications for the treatment of concomitant diseases could be continued in the usual dosage.

The clinical effectiveness of the treatment was determined using the following parameters:

, Assessment of the intensity of rest pain and stress pain by the patient using a 100 mm scale, where 0 means "no pain" and 100 "unbearable pain". The load was defined as the ascent and descent of a fixed landing.

, Assessment of the functional status of the knee using the Larson Score

, Assessment of bone marrow edema using MRI.

Adverse events and side effects were recorded as safety parameters. Known side effects of lloprost include symptoms such as headache, flushing, nausea, vomiting and diarrhea.

The course of the study was as follows:

1) Examination was six weeks ago. As a result of a 28-day treatment with oral lloprost, almost freedom from pain was achieved at rest and under stress in patients with osteonecrosis, the majority of whom had taken a variety of other drug combinations without success for several weeks before the start of the study. The effect on the pain was already detectable after 3 days of treatment and persisted 2 months after the end of the treatment. With the decrease in pain, complete regression of the bone marrow edema was recorded in MR control images of 44% of the patients.

Double-blind comparative study

To confirm the effect of oral lloprost on bone marrow edema and pain, a randomized, double-blind, comparative study of the Tramadol ^® opiate was performed in 41 patients with osteonecrosis or osteoarthritis of the knee from March 2001 to November 2002 according to the GCP guidelines.

All patients gave their prior written consent to participate in the study after being informed verbally and in writing about the nature, aim and course of the study. Patients of both sexes with rest pain due to osteonecrosis or osteoarthritis were included in the study if the following criteria were met:

• age between 19 and 60 years,

• Bone marrow edema diagnosed by MRI according to specified criteria. Treatment was either with Iloprost capsules or with Tramadol capsules that looked the same and were packaged and labeled in accordance with the applicable GLP rules. Each capsule contained either 50 μg lloprost or 50 mg Tramadol ^® .

During the first three days of treatment, the study medication was administered in a dose of 3x1 capsule per day, which was administered individually from day 4 onwards

Enhancement of therapy success (pain relief) to a maximum Dosage of 3x2 capsules a day could be increased. In the event of poor tolerance, the dosage could be reduced at any time to a minimum dose of 2x1 capsules a day.

The duration of treatment was one month, followed by a treatment-free follow-up period of two months. Pain-relieving drugs previously administered should be discontinued before the start of the study.

, Assessment of the intensity of rest pain and stress pain by the patient using a 100 mm scale, where 0 means "no pain" and 100 "unbearable pain".

, Assessment of the functional status of the knee using the Larson Score. Assessment of bone marrow edema using MRI.

Unwanted events and

Side effects recorded. Known side effects of lloprost are

Complaints such as headache, facial flushing, nausea, vomiting and diarrhea.

The course of the study was as follows:

1) Visits outside of the planned timeline could be made both during the treatment and during the follow-up examination.

2) End of study medication or premature termination of study medication.

3) End of alternative therapy or premature termination of alternative therapy.

4) Visit 6 took place on day 56 or after 4 treatment-free weeks.

5) Visit 7 took place on day 84 or after 8 treatment-free weeks.

6) urine strip test.

7) Examination can be done within 6 weeks before baseline.

In patients with osteonecrosis or osteoarthritis, oral lloprost caused bone marrow edema to regress in 53% of patients, whereas this was only the case in 19% of patients taking Tramadol ^® . This The difference was statistically significant (p = 0.0336, Fisher's exact test). This effect was accompanied by a significant pain relief as shown in the pilot study. In addition, a decrease in subchrondral lesions was found only under lloprost therapy and thus an indication of the restoration of structural integrity was given.

Claims

claims

1. Use of orally available prostacyclin derivatives of the general formula I

wherein

R ^{1 is} a hydrogen atom or a CrCio-alkyl radical,

A is a -CH ₂ -CH ₂ group, a trans -CH = CH group or a -C≡C group

W is a free or functionally modified hydroxymethylene group on the hydroxyl group, the hydroxyl group being in the α or β position,

X, Y independently of one another are a —CH ₂ - group or an oxygen atom,

Z is a hydrogen atom or a cyano group,

D is a straight-chain or branched saturated C -C ₅ alkylene group E is a -C≡C group or a direct bond,

R ^{2 is} a straight-chain or branched, saturated C 1 -C ₇ -alkyl group

R ^{3 is} a free or functionally modified hydroxy group, and all optically active forms, racemates, diastereomers, mixtures of diastereomers, their clathrate, and if R ^{1 is} hydrogen, their salts with physiologically compatible bases for the preparation of a medicament for the treatment of Diseases associated with bone marrow edema.

2. Use according to claim 1, characterized in that the prostazyclin derivatives of the formula I are present as cyclodextrin clathrate.

3. Use of orally available prostacyclin derivatives according to claim 1 or 2 for the manufacture of a medicament for the treatment of osteonecrosis.

4. Use of orally available prostacyclin derivatives according to claim 1 or 2 for the manufacture of a medicament for the treatment of osteoarthritis.

5. Use of orally available lloprost (5 - {(1S, 5S, 6R, 7R) -7-hydroxy-6- [(E) - (3R, 4RS) -3-hydroxy-4-methyl-oct-1- en-6-ynyl] bicyclo [3.3.0] octan-3-ylidene} pentanoic acid), cicaprost (5 - {(E) - (1 S, 5S, 6S, 7R) -7-hydroxy-6 - [( 3S, 4S) - 3-hydroxy-4-methyl-1, 6-nonadiinyl] bicyclo [3.3.0] oct-3-ylidene} -3-oxapentanoic acid), epoprostenol ((5Z, 9, 13E, 15S) -6,9-Epoxy-11, 15-dihydroxy-prosta-5,13-dien-1-acid), Beraprost (TRK 100), Ciprostene, Taprostene, Naxaprostene, CS 570, SC-39902, FCE-22509, OP 41483 or

RS 93427 according to claim 1 for the manufacture of a medicament for the treatment of diseases associated with bone marrow edema.

6. Use of orally available lloprost (5 - {(1S, 5S, 6R, 7R) -7-hydroxy-6- [(E) - (3R, 4RS) -3-hydroxy-4-methyl-oct-1- en-6-ynyl] bicyclo [3.3.0] octan-3-ylidene} pentanoic acid), cicaprost (5 - {(E) - (1S, 5S, 6S, 7R) -7-hydroxy-6 - [(3S , 4S) -

3-hydroxy-4-methyl-1, 6-nonadiinyl] bicyclo [3.3.0] oct-3-ylidene} -3-oxapentanoic acid), epoprostenol ((5Z, 9α, 13E, 15S) -6.9- Epoxy-11, 15-dihydroxy-prosta-5,13-diene-1-acid), Beraprost (TRK 100), Ciprostene, Taprostene, Naxaprostene, CS 570, SC-39902, FCE-22509, OP 41483 or RS 93427 according to Claim2 for the manufacture of a medicament for the

Treatment of osteonecrosis.

7. Use of orally available lloprost (5 - {(1S, 5S, 6R, 7R) -7-hydroxy-6- [(E) - (3R, 4RS) -3-hydroxy-4-methyl-oct-1- en-6-ynyl] bicyclo [3.3.0] octan-3-ylidene} pentanoic acid), cicaprost (5 - {(E) - (1 S, 5S, 6S, 7R) -7-hydroxy-6 - [( 3S, 4S) - 3-hydroxy-4-methyl-1, 6-nonadiinyl] bicyclo [3.3.0] oct-3-ylidene} -3- oxapentanoic acid), epoprostenol ((5Z, 9α, 13E, 15S) -6,9-epoxy-11, 15-dihydroxy-prosta-5,13-dien-1-acid), beraprost (TRK 100), ciprostenes, taprostenes, Naxaprostene, CS 570, SC-39902, FCE-22509, OP 41483 or RS 93427 according to claim 3 for the manufacture of a medicament for the treatment of osteoarthritis.

8. Use of lloprost-β-cyclodextrin clathrate according to claim 1 for the manufacture of a medicament for the treatment of diseases associated with bone marrow edema.

9. Use of lloprost-β-cyclodextrin clathrate according to claim 2 for the manufacture of a medicament for the treatment of osteonecrosis.

10. Use of lloprost-β-cyclodextrin clathrate according to claim 3 for the manufacture of a medicament for the treatment of osteoarthritis.