CA2016985C - Dehydrocholecalciferol derivatives - Google Patents
Dehydrocholecalciferol derivatives Download PDFInfo
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- CA2016985C CA2016985C CA002016985A CA2016985A CA2016985C CA 2016985 C CA2016985 C CA 2016985C CA 002016985 A CA002016985 A CA 002016985A CA 2016985 A CA2016985 A CA 2016985A CA 2016985 C CA2016985 C CA 2016985C
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- sebaceous gland
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- 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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/67—Vitamins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/008—Preparations for oily skin
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The novel use of compounds of formula (see formula I) wherein R is H or OH, A is -C~C-, -CH=CH- with E-configuration or -CH2CH2- and R" is H or, where A
is -C~C-, R" may also be deuterium, for the treatment of sebaceous gland diseases, such as seborrheic dermatitis and, particularly, acne: a corresponding method of treatment as well as pharmaceutical compositions and commercial packages containing such a compound.
Novel compounds of formula I, wherein R" is deuterium.
is -C~C-, R" may also be deuterium, for the treatment of sebaceous gland diseases, such as seborrheic dermatitis and, particularly, acne: a corresponding method of treatment as well as pharmaceutical compositions and commercial packages containing such a compound.
Novel compounds of formula I, wherein R" is deuterium.
Description
~.~1'.~98a The invention is based on the finding of novel physiological properties of dehydrocholecalciferol derivatives. Specifically, it has been found that the compounds of formula C (R.~ ) 3 ~ON
C (R.~ ) 3 I
HO
wherein R is H or OH, A is -C=C-, -CH=CH- with E-configuration or -CH2CH2- and R" is H or, where A
is -C=C-, R" may also be deuterium, are useful for the treatment of sebaceous gland diseases, such as acne and seborrheic dermatitis.
Among the compounds of formula I, those wherein R" is deuterium are novel and as such are part of the invention.
The deuterated compounds can be prepared in a manner similar to the non-deuterated compounds, e.g. as described in the European patent application No. 325 279, via intermediates of formula %, C (R~~ )3 ~A
., \OSi(R1,R2,R') II
C (R.~ ) 3 I ~'' C
M~/9.3.90 ~~1~985 wherein R" is as above. R1 and R3 are lower alkyl and R2 is lower alkyl, aryl or aryl-lower alkyl.
The invention relates to the above mentioned deuterated compounds, further to the use of the compounds of formula I
for the treatment of sebaceous gland diseases such as seborrheic dermatitits and, specifically, acne; to pharma-ceutical compositions in dosage unit form suitable for oral or topical administration for the above treatment, containing one or more compounds of formula I, as well as to commercial packages containing as active pharmaceutical ingredient one or more compounds of formula I, together with instcuctions for the use thereof as indicated above. The invention also relates to a method for treating the above--mentioned disease states by administration of a compound of formula I or a mixture of two or more compounds of formula I.
Compounds of formula I are compounds A to H as defined below:
A: 1a,25-dihydroxy-16-dehydrocholecalciferol;
B: 25-hydroxy-16-dehydrocholecalciferol;
C: 1a,25-dihydroxy-16,23E-bisdehydrocholecalciferol;
D: 25-hydroxy-16.23E-bisdehydrocholecalciferol:
E: 1a,25-dihydroxy-16-dehydro-23-d9.dehydrocholecalciferol;
F: 25-hydroxy-16-dehydro-23-didehydrocholecalciferol;
G: 26.26.26.27.27,27-hexadeutero-1a,25-dihydroxy-16-dehydco-23-didehydrocholecalciferol and H: 26,26,26.27,27,27-hexadeutero-25-hydroxy-16-dehydro-23-didehydrocholecalciferol.
The useful activity of compound of formula I as agents for the treatment of acne can be demonstrated by the follo-wing test procedures:
Sebaceous cells ate isolated from adult human sebaceous glands and cultured on a layer of mouse 3T3 fibroblasts in a ~~J~.~~~~~i __ 3 __ manner analogous to that described in Cell 6, 1975, 331-334 and In Vitro 22:3. 1986, Part II, p. 22a, abstract #46. It involves the separation of the epidermal layer from the dermis by an electrokeratome. The dermal tissue is then treated by enzymatic and mechanical methods, to generate a single cell suspension of sebaceous cells.
The cells are cultured in either Iscove~s medium containing 2% human serum, 8% fetal calf serum and 4 p,g/ml ~0 dexamethasone, or Isrove~s medium containing 10% fetal calf serum and 4 ug/ml dexamethasone.
Cells are plated in medium without a compound of the invention and then given the compound in fresh medium 24-48 ~5 hours after the initial plating. The cultures are given fresh medium, containing a compound of the invention, every 48 hours. On the day of harvesting, the cultures are rinsed with 0.03% EDTA in PBS, to remove only the 3T3 fibroblasts.
The remaining sebocyte colonies are incubated in 0.05%
20 trypsin/0.03% EDTA to create a single cell suspension of sebocytes. The cells are diluted and counted in a hemocyto-meter.
Stock solutions of the test compounds are made up as 25 10 2 M solutions in ethanol and then diluted to concen-trations of 10 6, 10 7, 10 8 and 109 M. Also tested for the inhibition of proliferation of sebaceous cells in vitro was 1a,25-dihydroxycholecalciferol (compound X in the tables below).
The results are given in Table 1 as the amount of compound necessary to inhibit the proliferation of the sebaceous cells by 50% as compared to a control. The control was a culture treated with diluent only.
~C)~.~~~~~
_ 4 _ Table 1 Comp_und R p, D E F
ED50 (uM) 0.005 0.001 >1 0.001 0.1.
The results demonstrate that the compounds of the invention inhibit human sebocyte proliferation in vitro and, therefore, are useful as agents for the treatment of acne.
Several compounds were evaluated for topical anti-acne activity in the hamster ear sebaceous gland model. 50 ul of a solution of the compounds in acetone, were applied daily to the dorsal side of the right ear of the hamster.
Control hamsters received 50 ul of acetone. The animals ~5 were sacrificed after 4 weeks. The ears were removed and processed for histological evaluation. The areas of the sebaceous glands were determined from the cross sections by image analysis.
20 In Table 2, the data are expressed as percent change from control animals of the hamster ear sebaceous gland size cross section.
Table 2 Compound Dose (ug/hamster) ~ Change D 0,10 -16 1.00 -16 10.00 -43 F 0.01 - g 0.10 -23 l.oo _40 10.00 -64 In order to evaluate the calcification of soft tissues by the compounds of the invention, rats were labelled with a subcutaneous injection of 40 uCi 45Ca. The compounds were then administered either subcutaneously or topically for four consecutive days. The rats were sacrificed one day after the last injection. The hearts and kidneys were removed and digested with nitric acid. An aliquot of the digest was counted in a scintillation counter. The calcifi-cation ratio (cpm of X - control cpm)/(cpm of compound - control cpm) is given below:
Table 3 Compound Subcutaneous Topical D >1400 >34 E 47 < 1 F >1400 >34 The effect of compounds of the invention on the sebaceous glands of the hamster ear after oral administra-tion of the compounds was evaluated. 200 ul of a compound of the invention was dissolved in propylene glycol, admini-stered daily to male Golden Syrian hamsters. The animals were sacrificed after 4 weeks and the ears were processed for histological evaluation. The area of the sebaceous glands was measured on histologically prepared cross sections of the eat by image analysis. The data obtained are given below as % change in hamster ear sebaceous gland size cross section:
Table 4 Compound Dose (ug/kg) % Change D 2.50 _15*
5.00 -22w*
10.00 _27www 20.00 -36***
F 0.05 -16w 0.50 _23**
5.00 -42w**
50.00 -55w**
w p <0.05: ww p <0.01; w** p <0.001 The above data demonstrate that compounds of the invention are useful as agents in the treatment of sebaceous gland diseases, such as acne or seborrheic dermatitits.
Moreover, they bring about less soft tissue calcification than does 1x,25-dihydroxycholecalciferol. Soft tissue calcification is an undesirable side effect in a compound to be used for treating sebaceous gland diseases.
The compounds of formula I can be administered topically or orally for the treatment of sebaceous gland diseases such as acne or seborrheic decmatitits. Thus, they can be admini-stered orally for the treatment of acne in humans at a dosage of about 0.7 to 700, preferably 7.0 to 70 ug pec day.
Oral dosage forms comprising compounds of formula I may be incorporated e.g. in capsules or tablets with pharma-ceutically acceptable carriers. Examples of such carrier materials which may be incorporated into capsules are binders, such as gum tragacanth or gelatin; excipients, such as dicalcium phosphate; disintegrating agents, such as corn starch: lubricants, such as magnesium stearate; sweetening __ agents, such as sucrose; flavoring agents, such as pepper-mint. Tablets may be coated with shellac, sugar or both. A
syrup or elixir may contain a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring agent.
Topical dosage forms comprising compounds of formula I
include ointments and creams encompassing formulations having oleaginous, adsorbable, water soluble and emulsion--0 -type bases, such as lanolin and polyethylene glycols.
Topical dosage forms also comprise gels, lotions, powders and aerosols.
Lotions, i.e. liquid preparations varying from simple y5 solutions to aqueous of hydroalcoholic preparations containing finely divided substances, can contain suspending or dispersing agents, such as cellulose derivatives, e.g.
ethyl or methyl cellulose; gelatin or gums, Which incor-porate the active ingredient in a vehicle made up of water, 20 alcohol or glycerin. Cels are semi-solid preparations made by gelling a solution or suspension of the active ingredient in a carrier vehicle. The vehicles, which can be hydrous or anhydrous, are gelled using a gelling agent, e.g. carboxy polymethylene, and neutralized to a proper gel consistency Z.5 with the use of alkalies, e.g. sodium hydroxide, or amines, such as polyethylenecocoamine.
The following Examples illustrate the composition of soft gelatine capsules for oral administ.cation and of a 30 topical cream:
_8_ 'Example A
mq/capsule Compound E 0.0001-0.010 Butylated hydroxytoluene 0.016 Butylated hydroxyanisole 0.016 Fractionated coconut oil 160.0 Example B
mg/g of cream Compound E 0.001-1.0 Cetyl alcohol 1.5 Stearyl alcohol 2.5 Sorbitan monostearate 2.0 Glyceryl monostearate and polyoxyethylene glycol stearate 4.0 Polysorbate 60 1.0 Mineral oil ~,0 Propylene glycol 5,0 Propylparaben 0.05 Butylated hydroxyanisole 0.05 Sorbitol solution 2.0 Edetate disodium 0.01 Methylparaben 0.18 Distilled water q.s. to 100 g
C (R.~ ) 3 I
HO
wherein R is H or OH, A is -C=C-, -CH=CH- with E-configuration or -CH2CH2- and R" is H or, where A
is -C=C-, R" may also be deuterium, are useful for the treatment of sebaceous gland diseases, such as acne and seborrheic dermatitis.
Among the compounds of formula I, those wherein R" is deuterium are novel and as such are part of the invention.
The deuterated compounds can be prepared in a manner similar to the non-deuterated compounds, e.g. as described in the European patent application No. 325 279, via intermediates of formula %, C (R~~ )3 ~A
., \OSi(R1,R2,R') II
C (R.~ ) 3 I ~'' C
M~/9.3.90 ~~1~985 wherein R" is as above. R1 and R3 are lower alkyl and R2 is lower alkyl, aryl or aryl-lower alkyl.
The invention relates to the above mentioned deuterated compounds, further to the use of the compounds of formula I
for the treatment of sebaceous gland diseases such as seborrheic dermatitits and, specifically, acne; to pharma-ceutical compositions in dosage unit form suitable for oral or topical administration for the above treatment, containing one or more compounds of formula I, as well as to commercial packages containing as active pharmaceutical ingredient one or more compounds of formula I, together with instcuctions for the use thereof as indicated above. The invention also relates to a method for treating the above--mentioned disease states by administration of a compound of formula I or a mixture of two or more compounds of formula I.
Compounds of formula I are compounds A to H as defined below:
A: 1a,25-dihydroxy-16-dehydrocholecalciferol;
B: 25-hydroxy-16-dehydrocholecalciferol;
C: 1a,25-dihydroxy-16,23E-bisdehydrocholecalciferol;
D: 25-hydroxy-16.23E-bisdehydrocholecalciferol:
E: 1a,25-dihydroxy-16-dehydro-23-d9.dehydrocholecalciferol;
F: 25-hydroxy-16-dehydro-23-didehydrocholecalciferol;
G: 26.26.26.27.27,27-hexadeutero-1a,25-dihydroxy-16-dehydco-23-didehydrocholecalciferol and H: 26,26,26.27,27,27-hexadeutero-25-hydroxy-16-dehydro-23-didehydrocholecalciferol.
The useful activity of compound of formula I as agents for the treatment of acne can be demonstrated by the follo-wing test procedures:
Sebaceous cells ate isolated from adult human sebaceous glands and cultured on a layer of mouse 3T3 fibroblasts in a ~~J~.~~~~~i __ 3 __ manner analogous to that described in Cell 6, 1975, 331-334 and In Vitro 22:3. 1986, Part II, p. 22a, abstract #46. It involves the separation of the epidermal layer from the dermis by an electrokeratome. The dermal tissue is then treated by enzymatic and mechanical methods, to generate a single cell suspension of sebaceous cells.
The cells are cultured in either Iscove~s medium containing 2% human serum, 8% fetal calf serum and 4 p,g/ml ~0 dexamethasone, or Isrove~s medium containing 10% fetal calf serum and 4 ug/ml dexamethasone.
Cells are plated in medium without a compound of the invention and then given the compound in fresh medium 24-48 ~5 hours after the initial plating. The cultures are given fresh medium, containing a compound of the invention, every 48 hours. On the day of harvesting, the cultures are rinsed with 0.03% EDTA in PBS, to remove only the 3T3 fibroblasts.
The remaining sebocyte colonies are incubated in 0.05%
20 trypsin/0.03% EDTA to create a single cell suspension of sebocytes. The cells are diluted and counted in a hemocyto-meter.
Stock solutions of the test compounds are made up as 25 10 2 M solutions in ethanol and then diluted to concen-trations of 10 6, 10 7, 10 8 and 109 M. Also tested for the inhibition of proliferation of sebaceous cells in vitro was 1a,25-dihydroxycholecalciferol (compound X in the tables below).
The results are given in Table 1 as the amount of compound necessary to inhibit the proliferation of the sebaceous cells by 50% as compared to a control. The control was a culture treated with diluent only.
~C)~.~~~~~
_ 4 _ Table 1 Comp_und R p, D E F
ED50 (uM) 0.005 0.001 >1 0.001 0.1.
The results demonstrate that the compounds of the invention inhibit human sebocyte proliferation in vitro and, therefore, are useful as agents for the treatment of acne.
Several compounds were evaluated for topical anti-acne activity in the hamster ear sebaceous gland model. 50 ul of a solution of the compounds in acetone, were applied daily to the dorsal side of the right ear of the hamster.
Control hamsters received 50 ul of acetone. The animals ~5 were sacrificed after 4 weeks. The ears were removed and processed for histological evaluation. The areas of the sebaceous glands were determined from the cross sections by image analysis.
20 In Table 2, the data are expressed as percent change from control animals of the hamster ear sebaceous gland size cross section.
Table 2 Compound Dose (ug/hamster) ~ Change D 0,10 -16 1.00 -16 10.00 -43 F 0.01 - g 0.10 -23 l.oo _40 10.00 -64 In order to evaluate the calcification of soft tissues by the compounds of the invention, rats were labelled with a subcutaneous injection of 40 uCi 45Ca. The compounds were then administered either subcutaneously or topically for four consecutive days. The rats were sacrificed one day after the last injection. The hearts and kidneys were removed and digested with nitric acid. An aliquot of the digest was counted in a scintillation counter. The calcifi-cation ratio (cpm of X - control cpm)/(cpm of compound - control cpm) is given below:
Table 3 Compound Subcutaneous Topical D >1400 >34 E 47 < 1 F >1400 >34 The effect of compounds of the invention on the sebaceous glands of the hamster ear after oral administra-tion of the compounds was evaluated. 200 ul of a compound of the invention was dissolved in propylene glycol, admini-stered daily to male Golden Syrian hamsters. The animals were sacrificed after 4 weeks and the ears were processed for histological evaluation. The area of the sebaceous glands was measured on histologically prepared cross sections of the eat by image analysis. The data obtained are given below as % change in hamster ear sebaceous gland size cross section:
Table 4 Compound Dose (ug/kg) % Change D 2.50 _15*
5.00 -22w*
10.00 _27www 20.00 -36***
F 0.05 -16w 0.50 _23**
5.00 -42w**
50.00 -55w**
w p <0.05: ww p <0.01; w** p <0.001 The above data demonstrate that compounds of the invention are useful as agents in the treatment of sebaceous gland diseases, such as acne or seborrheic dermatitits.
Moreover, they bring about less soft tissue calcification than does 1x,25-dihydroxycholecalciferol. Soft tissue calcification is an undesirable side effect in a compound to be used for treating sebaceous gland diseases.
The compounds of formula I can be administered topically or orally for the treatment of sebaceous gland diseases such as acne or seborrheic decmatitits. Thus, they can be admini-stered orally for the treatment of acne in humans at a dosage of about 0.7 to 700, preferably 7.0 to 70 ug pec day.
Oral dosage forms comprising compounds of formula I may be incorporated e.g. in capsules or tablets with pharma-ceutically acceptable carriers. Examples of such carrier materials which may be incorporated into capsules are binders, such as gum tragacanth or gelatin; excipients, such as dicalcium phosphate; disintegrating agents, such as corn starch: lubricants, such as magnesium stearate; sweetening __ agents, such as sucrose; flavoring agents, such as pepper-mint. Tablets may be coated with shellac, sugar or both. A
syrup or elixir may contain a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring agent.
Topical dosage forms comprising compounds of formula I
include ointments and creams encompassing formulations having oleaginous, adsorbable, water soluble and emulsion--0 -type bases, such as lanolin and polyethylene glycols.
Topical dosage forms also comprise gels, lotions, powders and aerosols.
Lotions, i.e. liquid preparations varying from simple y5 solutions to aqueous of hydroalcoholic preparations containing finely divided substances, can contain suspending or dispersing agents, such as cellulose derivatives, e.g.
ethyl or methyl cellulose; gelatin or gums, Which incor-porate the active ingredient in a vehicle made up of water, 20 alcohol or glycerin. Cels are semi-solid preparations made by gelling a solution or suspension of the active ingredient in a carrier vehicle. The vehicles, which can be hydrous or anhydrous, are gelled using a gelling agent, e.g. carboxy polymethylene, and neutralized to a proper gel consistency Z.5 with the use of alkalies, e.g. sodium hydroxide, or amines, such as polyethylenecocoamine.
The following Examples illustrate the composition of soft gelatine capsules for oral administ.cation and of a 30 topical cream:
_8_ 'Example A
mq/capsule Compound E 0.0001-0.010 Butylated hydroxytoluene 0.016 Butylated hydroxyanisole 0.016 Fractionated coconut oil 160.0 Example B
mg/g of cream Compound E 0.001-1.0 Cetyl alcohol 1.5 Stearyl alcohol 2.5 Sorbitan monostearate 2.0 Glyceryl monostearate and polyoxyethylene glycol stearate 4.0 Polysorbate 60 1.0 Mineral oil ~,0 Propylene glycol 5,0 Propylparaben 0.05 Butylated hydroxyanisole 0.05 Sorbitol solution 2.0 Edetate disodium 0.01 Methylparaben 0.18 Distilled water q.s. to 100 g
Claims (9)
1. The use of the compounds of Formula I
wherein R is H or OH, A is -C~C-, -CH=CH- with E-configuration or -CH2CH2-, and R" is H or, where A is -C~C-, R" may also be deuterium, for the treatment of sebaceous gland diseases.
wherein R is H or OH, A is -C~C-, -CH=CH- with E-configuration or -CH2CH2-, and R" is H or, where A is -C~C-, R" may also be deuterium, for the treatment of sebaceous gland diseases.
2. A use in accordance with claim 1, wherein R is H
or OH, A is -C~C-, and R" is deuterium.
or OH, A is -C~C-, and R" is deuterium.
3. A pharmaceutical composition in dosage unit form suitable for oral or topical administration for the use according to claim 1, containing as active pharmaceutical ingredient one or more compounds of Formula I according to claim 1, together with a pharmaceutically acceptable carrier, diluent, or excipient.
4. A commercial package containing as active pharmaceutical ingredient one or more compounds of Formula I, which compounds are defined in claim 1 or 2, together with instructions for the use thereof for sebaceous gland diseases.
5. The use of the compounds of Formula I as claimed in claim 1 or 2, wherein the disease is seborrheic dermatitis.
6. The use of the compounds of Formula I as claimed in claim 1 or 2 wherein the disease is acne.
7. The use of the compounds of Formula I, which compounds are defined in claim 1 or claim 2, for the preparation of a medicament for the treatment of sebaceous gland diseases.
8. A use as in claim 7 wherein the disease is seborrheic dermatitis.
9. A use as in claim 7 wherein the disease is acne.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US353,716 | 1982-03-01 | ||
| US35371689A | 1989-05-18 | 1989-05-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2016985A1 CA2016985A1 (en) | 1990-11-18 |
| CA2016985C true CA2016985C (en) | 2001-03-27 |
Family
ID=23390270
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002016985A Expired - Lifetime CA2016985C (en) | 1989-05-18 | 1990-05-17 | Dehydrocholecalciferol derivatives |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0398217B1 (en) |
| JP (1) | JPH0686381B2 (en) |
| AT (1) | ATE99942T1 (en) |
| AU (1) | AU636609B2 (en) |
| CA (1) | CA2016985C (en) |
| DE (1) | DE69005897D1 (en) |
| DK (1) | DK0398217T3 (en) |
| IE (1) | IE64186B1 (en) |
| NZ (1) | NZ233704A (en) |
| ZA (1) | ZA903758B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA8923B (en) * | 1988-01-20 | 1989-09-27 | Hoffmann La Roche | 16-dehydro-vitamin d3-derivatives |
| GB9004544D0 (en) * | 1990-03-01 | 1990-04-25 | Leo Pharm Prod Ltd | Novel treatment ii |
| GB9017890D0 (en) * | 1990-08-15 | 1990-09-26 | Leo Pharm Prod Ltd | Chemical compounds i |
| IL103224A (en) * | 1992-09-18 | 1998-08-16 | Teva Pharma | Stabilized pharmaceutical compositions containing derivatives of vitamins d2 and d3 |
| TW267161B (en) * | 1992-11-20 | 1996-01-01 | Hoffmann La Roche | |
| US5428029A (en) * | 1993-11-24 | 1995-06-27 | Hoffmann-La Roche Inc. | Vitamin D3 fluorinated analogs |
| AU708679B2 (en) * | 1996-03-21 | 1999-08-12 | F. Hoffmann-La Roche Ag | 1,25-dihydroxy-16,22,23-trisdehydro-cholecalciferol derivatives |
| GB9625271D0 (en) * | 1996-12-04 | 1997-01-22 | Leo Pharm Prod Ltd | Chemical compounds |
| EP0884308B1 (en) * | 1997-05-02 | 2003-04-16 | Duphar International Research B.V | A method of preparing 16-dehydro vitamin D compounds |
| WO2005074389A2 (en) * | 2004-02-03 | 2005-08-18 | Chugai Pharmaceutical Co Ltd | Process for the synthesis of vitamin d compounds and intermediates for the synthesis of the compounds |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4610978A (en) * | 1983-03-22 | 1986-09-09 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Compositions containing 1α-hydroxycholecalciferol for topical treatment of skin disorders and methods employing same |
| EP0215956A4 (en) * | 1985-03-14 | 1988-09-07 | Chugai Pharmaceutical Co Ltd | Composition for treating skin disease. |
| US4898855A (en) * | 1987-09-14 | 1990-02-06 | Hoffman-La Roche Inc. | Deuterated analogs of 1,25-dihydroxycholecalciferol |
| ZA8923B (en) * | 1988-01-20 | 1989-09-27 | Hoffmann La Roche | 16-dehydro-vitamin d3-derivatives |
| US4804502A (en) * | 1988-01-20 | 1989-02-14 | Hoffmann-La Roche Inc. | Vitamin D compounds |
-
1990
- 1990-05-14 DE DE90109032T patent/DE69005897D1/en not_active Expired - Fee Related
- 1990-05-14 EP EP90109032A patent/EP0398217B1/en not_active Expired - Lifetime
- 1990-05-14 DK DK90109032.4T patent/DK0398217T3/en active
- 1990-05-14 AT AT90109032T patent/ATE99942T1/en not_active IP Right Cessation
- 1990-05-16 NZ NZ233704A patent/NZ233704A/en unknown
- 1990-05-16 ZA ZA903758A patent/ZA903758B/en unknown
- 1990-05-17 IE IE178090A patent/IE64186B1/en unknown
- 1990-05-17 AU AU55165/90A patent/AU636609B2/en not_active Ceased
- 1990-05-17 JP JP2128107A patent/JPH0686381B2/en not_active Expired - Fee Related
- 1990-05-17 CA CA002016985A patent/CA2016985C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| NZ233704A (en) | 1992-11-25 |
| IE901780L (en) | 1990-11-18 |
| AU636609B2 (en) | 1993-05-06 |
| JPH0317019A (en) | 1991-01-25 |
| CA2016985A1 (en) | 1990-11-18 |
| ATE99942T1 (en) | 1994-01-15 |
| IE64186B1 (en) | 1995-07-12 |
| EP0398217A1 (en) | 1990-11-22 |
| AU5516590A (en) | 1990-11-22 |
| DE69005897D1 (en) | 1994-02-24 |
| ZA903758B (en) | 1992-01-29 |
| EP0398217B1 (en) | 1994-01-12 |
| JPH0686381B2 (en) | 1994-11-02 |
| DK0398217T3 (en) | 1994-02-14 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed | ||
| MKEC | Expiry (correction) |
Effective date: 20121202 |