CA2617690A1 - Treatment of tumours with ikk-.beta. inhibitors - Google Patents
Treatment of tumours with ikk-.beta. inhibitors Download PDFInfo
- Publication number
- CA2617690A1 CA2617690A1 CA002617690A CA2617690A CA2617690A1 CA 2617690 A1 CA2617690 A1 CA 2617690A1 CA 002617690 A CA002617690 A CA 002617690A CA 2617690 A CA2617690 A CA 2617690A CA 2617690 A1 CA2617690 A1 CA 2617690A1
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- CA
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- Prior art keywords
- tumours
- treatment
- medicaments
- compound
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The application relates to the use of an IKK-beta inhibitor through production of medicaments for treating tumours, and to medicaments comprising the said IKK-beta inhibitor.
Description
BHC 05 1 045-Foreign countries CA 02617690 2008-02-01 Treatment of tumours with IKK-R inhibitors The application relates to the use of an IKK-beta inhibitor for the production of medicaments for treating of tumours, and medicaments comprising this IKK-beta inhibitor.
The treatment of tumour diseases of the skin is a great and, especially conceming metastasizing melanoma, unsatisfactorily solved medical problem.
Here, by far the most frequent tumours of fair-skinned people are epithelial skin tumours, such as, for example, basal cell carcinoma and prickle-cell carcinoma including their pre-invasive early stages (actinic keratoses or carcinoma in situ).
While basalioma and prickle-cell carcinoma together make up approximately 15 per cent of all malignant tumours, melanoma occurs far more rarely. According to details of the cancer umbrella documentation in the Robert-Koch Institute, in Germany in the year 2000 just under 11 500 illnesses occurred, in the USA the estimated number of new illnesses in the year 2003 was approximately 54 000. The prognosis of metastasizing melanoma is still unfavourable and in general there is a small prospect of a permanent cure.
The most important mechanisms which are responsible for the malignancy of metastasizing skin tumours include resistance to apoptosis (programmed cell death).
Therefore therapeutic strategies or substances which can again induce apoptosis in tumour cells are of outstanding importance for successful therapies of tumours of the skin (1).
The object of the invention was thus the development of a novel therapeutic active in tumorous skin diseases, which does not have the disadvantages of systemic chemotherapy (e.g. extensive side effects, clinical improvement lasting for only a short time, administration which is often not simple) and which induces apoptosis in cancer cells.
It has now surprisingly been found that the compound of the formula (I) NH HCI
N N_~_O
H
OH
and/or its salts, hydrates and solvates, which are potent, competitive and selective inhibitors of BHC 05 1 045-Foreign countries CA 02617690 2008-02-01 IKK-beta kinase, can be used for treating tumours and their early stages. The hydrochloride of the compound of the formula (I) is preferred.
The compound of the formula (1) and/or its salts, hydrates and solvates, have an apoptosis-inducing action here in the melanoma cell line A375, which reacts sensitively to various pro-apoptotic stimuli. If caspases (enzymes which mediate the intracellular signal pathways of apoptosis) in A375 cells, which react sensitively to pro-apoptotic stimuli with apoptosis, are blocked with the inhibitor zVAD, the apoptosis induced in these cells by stimulation with CH-11 is suppressed.
However, the addition of the compound of the formula (I) and/or its salts, hydrates and solvates is able to induce apoptosis again, which indicates alternative ways of induction of apoptosis.
In particular, it has been found that the compound of the formula (I) and/or its salts, hydrates and solvates can be employed for the treatment of skin tumours such as, for example, basalioma, prickle-cell carcinoma, melanoma, cutaneous manifestations of T-cell lymphomas, cutaneous metastases of other tumours and their early stages, such as, in particular, actinic keratoses and Bowen's disease.
Treatment is preferably carried out systemically and/or topically. In the case of systemic treatment, administration of the active substance can be carried out orally using tablets, juices, emulsions, capsules or other pharmaceutical preparations. Systemic treatment can also be carried out parenterally (intravenously, subcutaneously). Topical treatment is carried out by application of the active substance in suitable formulations to the affected skin (skin lesion) or in the vicinity of the skin lesions to be treated. The formulations used can be ointments, creams, powders, emulsions, solutions. Moreover, patches or dressings impregnated with active substance can be used. Systemic and/or topical treatment can be carried out according to various time schemes (single treatment up to several times daily over a fixed time period).
The topical treatment of tumours of the eye and metastases of other tumours on the eye and of tumours of the ear (and metastases of other tumours on the ear) and of tumours of the external genitalia (and metastases of other tumours on the external genitalia) is preferred. This includes tumours which are caused by virus infections (e.g. genital warts caused by infection with different types of the human papilloma virus, Kaposi's sarcoma of the skin and mucous membrane, epidermodysplasia verucciformis or other neoplastic changes).
The invention further relates to combinations of the compound of the formula (I) and/or its salts, hydrates and solvates with at least one other active substance whicli can be employed for the treatment of tumours, in particular with dacarbacin (DTIC-DOME), doxorubicin (Doxil), interferons (e.g. interferon alfa-2b, intron-A), imiquimod (Aldara, R-837, S-26308), resiquimod BHC 05 1 045-Foreign countries CA 02617690 2008-02-01 (R-848, S-28436), interleukin 2 (IL-2, proleukin, aldesleukin), retinoids, temozolomide and/or therapeutic melanoma vaccines (e.g. prepared or synthetic antigens, or transfected cells), for the treatment of tumours of the skin.
Combined treatment with the compound of the formula (I) and/or its salts, hydrates and solvates, with radiotherapies, irradiation therapy with visible light, ionizing radiation, UV radiation, photodynamic therapy is likewise preferred.
Topical treatment of tumours of the urogenital system, e.g. by instillation of a solution or of a suspension of the compound of the formula (I) or other suitable pharmaceutical preparations of the compound of the formula (I) (e.g. emulsions, gels) is likewise possible.
The following examples serve to illustrate the invention.
BHC 05 1 045-Foreign countries CA 02617690 2008-02-01 1. IKK beta-kinase assay:
The kinase activity of human IKK-beta (7 nM) is measured at different concentrations of [y33P]ATP and GST-IxBa (1-54) substrate in the presence of the compound of the formula (I) =
substance A. Here, fixed concentrations of 2 M GST-IKBa (1-54) (Figure 3 A) or 5 M ATP
(Figure 3 B) are chosen. The mixture is incubated at 25 C for 30 minutes and the reaction is subsequently stopped by addition of EDTA. Using TCA, the reaction is precipitated in a filter plate, Microscint PS (Packard) is added and the amount of 33P incorporated into GST-IKBa (1-54) is determined using a TopCount (Packard).
2. Measurement of apoptosis activity in melanoma cell lines A375 cells are plated out in a density of 3x106 cells and Mel2a cells in a density of 3x103 cells in triplets in cell culture dishes and incubated with the compound of the formula (I) or the corresponding controls, 0.5 g/ml of anti-CD-95 (CH-11, Upstate), 6.6 M zVAD
(R&D Systems) for the period of time indicated in Figures 3 to 5. Addition is carried out 30 minutes before the second substance. After this, apoptosis detection is carried out using a Cell Death Detection ELISAPLUS (Roche Diagnostics) according to the manufacturer's instructions.
A375 and Mel2a cells are established melanoma cell lines.
BHC 05 1 045-Foreign countries CA 02617690 2008-02-01 A 0.16 IATP] (uM) 0.14 ~ 2aD
0.12 ~ 13.3 0.1 ~ ~ = 8.9 QA8 0 5.5 4a a ne 2&
0 04 9 ,8 0J]2 -a 5 10 15 20 26 30 Conoentration A (nM) 0.8 [GST-IkBa (9-54)J
B 0.7 (uM) u 12 0.6 0.5 ~ 0,8 p 0.6 0.4 0 oA
0.3 a.2J:Y 0 -5 0 5 10 15 20 2!
Concentration A. (n M ) Figure 2: Inhibition of human recombinant IKK-beta by compound of the formula (I) Apoptosis assay on melanoma cell line A375 after 24h incubation d.DD
SD
~
a ].DD
q Z.SD
Z.DD
1.SD
p, 1.DD
cn D. SD
D.DD
Conj=1 D.1% S7.EE 25.914 1].E4 5.78 1.]8 D.1]$ 0.DD552 CH 11 5 eay fi5-58ii Coruu_ntrati~ninthe irnibationmedu= CNMI
BHC 05 1 045-Foreign countriescA 02617690 2008-02-01 Figure 3: Detection of apoptosis in A375 melanoma cells. Substance A induces dose-dependent apoptosis. Positive control: The antibody CH-11 stimulates Fas (CD-95) and thus induces apoptosis.
Apoptosis assay on melanoma cell line MeI2a after 24h incubation 3.00 --- - -- ~... - -----~
_. _ __ ....._.
o 2.00 ±...._ .... _. .....m... . _ _ ... . _.. ... .. - -~ ~_....__,.....
p ............. ,.. _... _ -..._ -..__. ..... ... . .._.... _.. _._.
v 2.50 ~..__ - .......... ......._. .. . ...,..... -.._... ........... . ..._...
_.._...
4( . < ...-. .-_....._~ ..........__.... I 4---- ~ . .-_ ,.. .õ,., -,-1,00 m I i P. 0.50 -.....__ ..- _-a.on ---.~~...____ Control 0.1% 0.2% 57.88 28.94 13.89 5.78 1.38 0.138 0.00552 DMSO PMSO
eay 55-5811 Coxrocentrati,an in tle ix1cubation xnednun [NMl Figure 4: Mel-2a cells are resistant to stimulation by Fas (CD-95). Substance A, however, induced dose-dependent apoptosis in these cells, which points to a receptor-independent mechanism.
BHC 05 1 045-Foreign countriesCA 02617690 2008-02-01 Apoptosis assay on melanoma cell line A375 after 12h incubation ].66 2.S6 P.
p Z.D6 N
l7 ~ 1.56 1.DD
P~sz C. S6 6.66 ~Of1tY4~ DM54 6."% Z-V.4D CH11 Z-VAD+CH11 Z-VAL=+ZB,SW 2E.94 &ay 65-5911 Concentration in the incubatwn niednlnt [NM]
Figure 5: Inhibition of caspases by the inhibitor zVAD in apoptosis-sensitive (CH-11) cells. The addition of A again induces the apoptosis which is inhibited by zVAD.
The treatment of tumour diseases of the skin is a great and, especially conceming metastasizing melanoma, unsatisfactorily solved medical problem.
Here, by far the most frequent tumours of fair-skinned people are epithelial skin tumours, such as, for example, basal cell carcinoma and prickle-cell carcinoma including their pre-invasive early stages (actinic keratoses or carcinoma in situ).
While basalioma and prickle-cell carcinoma together make up approximately 15 per cent of all malignant tumours, melanoma occurs far more rarely. According to details of the cancer umbrella documentation in the Robert-Koch Institute, in Germany in the year 2000 just under 11 500 illnesses occurred, in the USA the estimated number of new illnesses in the year 2003 was approximately 54 000. The prognosis of metastasizing melanoma is still unfavourable and in general there is a small prospect of a permanent cure.
The most important mechanisms which are responsible for the malignancy of metastasizing skin tumours include resistance to apoptosis (programmed cell death).
Therefore therapeutic strategies or substances which can again induce apoptosis in tumour cells are of outstanding importance for successful therapies of tumours of the skin (1).
The object of the invention was thus the development of a novel therapeutic active in tumorous skin diseases, which does not have the disadvantages of systemic chemotherapy (e.g. extensive side effects, clinical improvement lasting for only a short time, administration which is often not simple) and which induces apoptosis in cancer cells.
It has now surprisingly been found that the compound of the formula (I) NH HCI
N N_~_O
H
OH
and/or its salts, hydrates and solvates, which are potent, competitive and selective inhibitors of BHC 05 1 045-Foreign countries CA 02617690 2008-02-01 IKK-beta kinase, can be used for treating tumours and their early stages. The hydrochloride of the compound of the formula (I) is preferred.
The compound of the formula (1) and/or its salts, hydrates and solvates, have an apoptosis-inducing action here in the melanoma cell line A375, which reacts sensitively to various pro-apoptotic stimuli. If caspases (enzymes which mediate the intracellular signal pathways of apoptosis) in A375 cells, which react sensitively to pro-apoptotic stimuli with apoptosis, are blocked with the inhibitor zVAD, the apoptosis induced in these cells by stimulation with CH-11 is suppressed.
However, the addition of the compound of the formula (I) and/or its salts, hydrates and solvates is able to induce apoptosis again, which indicates alternative ways of induction of apoptosis.
In particular, it has been found that the compound of the formula (I) and/or its salts, hydrates and solvates can be employed for the treatment of skin tumours such as, for example, basalioma, prickle-cell carcinoma, melanoma, cutaneous manifestations of T-cell lymphomas, cutaneous metastases of other tumours and their early stages, such as, in particular, actinic keratoses and Bowen's disease.
Treatment is preferably carried out systemically and/or topically. In the case of systemic treatment, administration of the active substance can be carried out orally using tablets, juices, emulsions, capsules or other pharmaceutical preparations. Systemic treatment can also be carried out parenterally (intravenously, subcutaneously). Topical treatment is carried out by application of the active substance in suitable formulations to the affected skin (skin lesion) or in the vicinity of the skin lesions to be treated. The formulations used can be ointments, creams, powders, emulsions, solutions. Moreover, patches or dressings impregnated with active substance can be used. Systemic and/or topical treatment can be carried out according to various time schemes (single treatment up to several times daily over a fixed time period).
The topical treatment of tumours of the eye and metastases of other tumours on the eye and of tumours of the ear (and metastases of other tumours on the ear) and of tumours of the external genitalia (and metastases of other tumours on the external genitalia) is preferred. This includes tumours which are caused by virus infections (e.g. genital warts caused by infection with different types of the human papilloma virus, Kaposi's sarcoma of the skin and mucous membrane, epidermodysplasia verucciformis or other neoplastic changes).
The invention further relates to combinations of the compound of the formula (I) and/or its salts, hydrates and solvates with at least one other active substance whicli can be employed for the treatment of tumours, in particular with dacarbacin (DTIC-DOME), doxorubicin (Doxil), interferons (e.g. interferon alfa-2b, intron-A), imiquimod (Aldara, R-837, S-26308), resiquimod BHC 05 1 045-Foreign countries CA 02617690 2008-02-01 (R-848, S-28436), interleukin 2 (IL-2, proleukin, aldesleukin), retinoids, temozolomide and/or therapeutic melanoma vaccines (e.g. prepared or synthetic antigens, or transfected cells), for the treatment of tumours of the skin.
Combined treatment with the compound of the formula (I) and/or its salts, hydrates and solvates, with radiotherapies, irradiation therapy with visible light, ionizing radiation, UV radiation, photodynamic therapy is likewise preferred.
Topical treatment of tumours of the urogenital system, e.g. by instillation of a solution or of a suspension of the compound of the formula (I) or other suitable pharmaceutical preparations of the compound of the formula (I) (e.g. emulsions, gels) is likewise possible.
The following examples serve to illustrate the invention.
BHC 05 1 045-Foreign countries CA 02617690 2008-02-01 1. IKK beta-kinase assay:
The kinase activity of human IKK-beta (7 nM) is measured at different concentrations of [y33P]ATP and GST-IxBa (1-54) substrate in the presence of the compound of the formula (I) =
substance A. Here, fixed concentrations of 2 M GST-IKBa (1-54) (Figure 3 A) or 5 M ATP
(Figure 3 B) are chosen. The mixture is incubated at 25 C for 30 minutes and the reaction is subsequently stopped by addition of EDTA. Using TCA, the reaction is precipitated in a filter plate, Microscint PS (Packard) is added and the amount of 33P incorporated into GST-IKBa (1-54) is determined using a TopCount (Packard).
2. Measurement of apoptosis activity in melanoma cell lines A375 cells are plated out in a density of 3x106 cells and Mel2a cells in a density of 3x103 cells in triplets in cell culture dishes and incubated with the compound of the formula (I) or the corresponding controls, 0.5 g/ml of anti-CD-95 (CH-11, Upstate), 6.6 M zVAD
(R&D Systems) for the period of time indicated in Figures 3 to 5. Addition is carried out 30 minutes before the second substance. After this, apoptosis detection is carried out using a Cell Death Detection ELISAPLUS (Roche Diagnostics) according to the manufacturer's instructions.
A375 and Mel2a cells are established melanoma cell lines.
BHC 05 1 045-Foreign countries CA 02617690 2008-02-01 A 0.16 IATP] (uM) 0.14 ~ 2aD
0.12 ~ 13.3 0.1 ~ ~ = 8.9 QA8 0 5.5 4a a ne 2&
0 04 9 ,8 0J]2 -a 5 10 15 20 26 30 Conoentration A (nM) 0.8 [GST-IkBa (9-54)J
B 0.7 (uM) u 12 0.6 0.5 ~ 0,8 p 0.6 0.4 0 oA
0.3 a.2J:Y 0 -5 0 5 10 15 20 2!
Concentration A. (n M ) Figure 2: Inhibition of human recombinant IKK-beta by compound of the formula (I) Apoptosis assay on melanoma cell line A375 after 24h incubation d.DD
SD
~
a ].DD
q Z.SD
Z.DD
1.SD
p, 1.DD
cn D. SD
D.DD
Conj=1 D.1% S7.EE 25.914 1].E4 5.78 1.]8 D.1]$ 0.DD552 CH 11 5 eay fi5-58ii Coruu_ntrati~ninthe irnibationmedu= CNMI
BHC 05 1 045-Foreign countriescA 02617690 2008-02-01 Figure 3: Detection of apoptosis in A375 melanoma cells. Substance A induces dose-dependent apoptosis. Positive control: The antibody CH-11 stimulates Fas (CD-95) and thus induces apoptosis.
Apoptosis assay on melanoma cell line MeI2a after 24h incubation 3.00 --- - -- ~... - -----~
_. _ __ ....._.
o 2.00 ±...._ .... _. .....m... . _ _ ... . _.. ... .. - -~ ~_....__,.....
p ............. ,.. _... _ -..._ -..__. ..... ... . .._.... _.. _._.
v 2.50 ~..__ - .......... ......._. .. . ...,..... -.._... ........... . ..._...
_.._...
4( . < ...-. .-_....._~ ..........__.... I 4---- ~ . .-_ ,.. .õ,., -,-1,00 m I i P. 0.50 -.....__ ..- _-a.on ---.~~...____ Control 0.1% 0.2% 57.88 28.94 13.89 5.78 1.38 0.138 0.00552 DMSO PMSO
eay 55-5811 Coxrocentrati,an in tle ix1cubation xnednun [NMl Figure 4: Mel-2a cells are resistant to stimulation by Fas (CD-95). Substance A, however, induced dose-dependent apoptosis in these cells, which points to a receptor-independent mechanism.
BHC 05 1 045-Foreign countriesCA 02617690 2008-02-01 Apoptosis assay on melanoma cell line A375 after 12h incubation ].66 2.S6 P.
p Z.D6 N
l7 ~ 1.56 1.DD
P~sz C. S6 6.66 ~Of1tY4~ DM54 6."% Z-V.4D CH11 Z-VAD+CH11 Z-VAL=+ZB,SW 2E.94 &ay 65-5911 Concentration in the incubatwn niednlnt [NM]
Figure 5: Inhibition of caspases by the inhibitor zVAD in apoptosis-sensitive (CH-11) cells. The addition of A again induces the apoptosis which is inhibited by zVAD.
Claims (8)
1. Use of the compound of the formula (I) and/or its salts, hydrates and solvates, for the production of medicaments for treating tumours and their early stages.
2. Use according to Claim 1, for the treatment of skin tumours and their early stages.
3. Use according to Claim 1, for the production of systemic medicaments.
4. Use according to Claim 1, for the production of topical medicaments.
5. Use according to Claim 1, for the production of medicaments for the topical treatment of tumours of the eye and metastases of other tumours on the eye, of tumours of the ear and metastases of other tumours on the ear, of tumours of the external genitalia and metastases of other tumours on the external genitalia.
6. Medicaments for the treatments of tumours and their early stages comprising a compound of the formula (I) and/or its salts, hydrates and solvates.
7. Medicaments for the treatment of tumours of the skin and their early stages comprising a compound of the formula (I) and/or its salts, hydrates and solvates.
8. Medicaments comprising a compound of the formula (I) and/or its salts, hydrates and solvates, in combination with at least one other active substance which can be employed for the treatment of tumours.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102005036655.4 | 2005-08-04 | ||
| DE102005036655A DE102005036655A1 (en) | 2005-08-04 | 2005-08-04 | Treatment of tumors with IKK-ß inhibitors |
| PCT/EP2006/007201 WO2007014652A1 (en) | 2005-08-04 | 2006-07-21 | TREATMENT OF TUMOURS WITH IKK-ß INHIBITORS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2617690A1 true CA2617690A1 (en) | 2007-02-08 |
Family
ID=37075493
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002617690A Abandoned CA2617690A1 (en) | 2005-08-04 | 2006-07-21 | Treatment of tumours with ikk-.beta. inhibitors |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1912652A1 (en) |
| JP (1) | JP2009502995A (en) |
| CA (1) | CA2617690A1 (en) |
| DE (1) | DE102005036655A1 (en) |
| WO (1) | WO2007014652A1 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4272338B2 (en) * | 2000-09-22 | 2009-06-03 | バイエル アクチェンゲゼルシャフト | Pyridine derivatives |
| JP2003277383A (en) * | 2002-03-14 | 2003-10-02 | Bayer Ag | Optically active pyridine derivative and medicine containing the same |
-
2005
- 2005-08-04 DE DE102005036655A patent/DE102005036655A1/en not_active Withdrawn
-
2006
- 2006-07-21 CA CA002617690A patent/CA2617690A1/en not_active Abandoned
- 2006-07-21 EP EP06762748A patent/EP1912652A1/en not_active Withdrawn
- 2006-07-21 WO PCT/EP2006/007201 patent/WO2007014652A1/en active Application Filing
- 2006-07-21 JP JP2008524393A patent/JP2009502995A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JP2009502995A (en) | 2009-01-29 |
| EP1912652A1 (en) | 2008-04-23 |
| WO2007014652A1 (en) | 2007-02-08 |
| DE102005036655A1 (en) | 2007-02-08 |
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