AU636609B2 - Dehydrocholecalciferol derivatives - Google Patents
Dehydrocholecalciferol derivatives Download PDFInfo
- Publication number
- AU636609B2 AU636609B2 AU55165/90A AU5516590A AU636609B2 AU 636609 B2 AU636609 B2 AU 636609B2 AU 55165/90 A AU55165/90 A AU 55165/90A AU 5516590 A AU5516590 A AU 5516590A AU 636609 B2 AU636609 B2 AU 636609B2
- Authority
- AU
- Australia
- Prior art keywords
- compound
- formula
- compounds
- deuterium
- dehydrocholecalciferol
- 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.)
- Ceased
Links
Classifications
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Birds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Cosmetics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Abstract
The use of dehydrocholecalciferal derivs. of formula (I) to make pharmaceuticals for treating diseases of the sebaceous glands is new. (Where R = H or OH; A = CC, (E)-CH=CH or CH2CH2; R'' = H or, where A = C=C, it can also be deuterium). (I) are new cpds. where R'' = deuterium.
Description
C 6 S F Ref: 128409 FORM COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION
(ORIGINAL)
FOR OFFICE USE: 1 I
'S
I I Class Int Class Complete Specification Lodged: Accepted: Published: Priority: Related Art:
IS
Si Name and Address of Applicant: Address for Service: F.Hoffmann-La Roche AG 124 Grenzacherstrasse CH-4002, Basel
SNITZERLAND
Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia I I Iti S I I
II'
Complete Specification for the invention entitled: Denydrocholecalciferol Derivatives The following statement is a full description of this invention, including the best method of performing it known to me/us
I
5845/3
_J
'I ~armri--nrsnriiii;t The invention is based on the finding of novel physiological properties of dehydrocholecalciferol derivatives. Specifically, it has been found that the compounds of formula I A C(R') 3
S/OH
C(R')3
H
HO" R wherein R is H or OH, A is -CH=CH- with E-configuration or -CH 2
CH
2 and R" is H or, where A is R" may also be deuterium, are useful for the treatment of sebaceous gland diseases, such as acne and seborrheic dermatitis.
According to a first embodiment of the present invention there is provided a method of treating sebaceous gland diseases in a patient requiring or desiring such treatment, comprising administering to said patient an effective amount of a compound of formula o A C(R 3
S
H
OH
C(R")
3
H
0 00
I
HO' R 0 0 1 wherein R is H or OH, A is -CH=CH- with E-configuration or -CH 2
CH
2 and R" is H or, where A is R" may also be deuterium.
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 A C(R") 3 "KOSi(R 1
,R
2
,R
3
C(R')
3 H I SILikb 00035:JOC a of 3 Iy| -2- 1 3 wherein R" is as above, R and R are lower alkyl and R is lower alkyl, aryl or aryl-lower alkyl.
P#
rI
II~
I t t *9 4 relt I 44
I
It t I 4
T
II. I I t 9 t t I tL i l t 1 41 i I 44* 1 t t t 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 pharmaceutical compositions in dosage unit form suitable for oral or topical administration for the above treatment, 10 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 instructions 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 4 4 I t 4 1 I t 25 A: la,25-dihydroxy-16-dehydrocholecalciferol; B: 25-hydroxy-16-dehydrocholecalciferol; C: la,25-dihydroxy-16,23E-bisdehydrocholecalciferol; D: 25-hydroxy-16,23E-bisdehydrocholecalciferol; E: la,25-dihydroxy-16-dehydro-23-didehydrocholecalciferol; F: 25-hydroxy-16-dehydro-23-didehydrocholecalciferol; G: 26,26,26,27,27,27-hexadeutero-la,25-dihydroxy-16dehydro-23-didehydrocholecalciferol and H: 26,26,26,27,27,27-hexadeutero-25-hydroxy-16-dehydro-23didehydrocholecalciferol.
The useful activity of compound of formula I as agents for the treatment of acne can be demonstrated by the following test procedures: Sebaceous cells are isolated from adult human sebaceous glands and cultured on a layer of mouse 3T3 fibroblasts in a .I 3 4 44 4I t 4t I
I
4r I 4 4r i I 444 I 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 ig/ml 10 dexamethasone, or Iscove's medium containing 10% fetal calf serum and 4 ig/ml dexamethasone.
Cells are plated in medium without a compound of the invention and then given the compound in fresh medium 24-48 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% trypsin/0.03% EDTA to create a single cell suspension of sebocytes. The cells are diluted and counted in a hemocytometer.
Stock solutions of the test compounds are made up as 10 2 M solutions in ethanol and then diluted to concentrations of 10 10 10 and 10 9 M. Also tested for the inhibition of proliferation of sebaceous cells in vitro was la,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.
I 4 Table 1 Compund
(IM)
X A 0.005 0.001 0.001 0.1 9 o O I 9 0 94 4d 4 4I 40*0 49 01 994 9) 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 .1 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 p. of acetone. The animals 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.
In Table 2, the data are expressed as percent change from control animals of the hamster ear sebaceous gland size cross section.
*4 4 0 Ilt 4 0 40000 Table 2 Compound Dose (ig/hamster) Change 0.10 1.00 10.00 0.01 0.10 1.00 10.00 -16 -16 -43 8 -23 -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 IiCi 4SCa. 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 calcification ratio (cpm of X control cpm)/(cpm of compound control cpm) is given below: Table 3 compound Subcutaneous Topical X11 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 administration of the compounds was evaluated. 200 lil of a compound of the invention was dissolved in propylene glycol, administered 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 ear by image analysis. The data obtained are given below as change in hamster ear sebaceous gland size cross section: 6 Table 4 Compound Dose (ug/kg) Change D 2.50 5.00 -22** 10.00 20.00 1F 0.05 -16* O 10 0.50 -23** 5.00 50.00 P to o o, p <0.05; p <0.01; 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.
1 Moreover, they bring about less soft tissue calcification than does la,25-dihydroxycholecalciferol. Soft tissue o o calcification is an undesirable side effect in a compound to 1 be used for treating sebaceous gland diseases.
The compounds of formula I can be administered topically 25 or orally for the treatment of sebaceous gland diseases such as acne or seborrheic dermatitits. Thus, they can be administered orally for the treatment of acne in humans at a dosage of about 0.7 to 700, preferably 7.0 to 70 ig per day.
Oral dosage forms comprising compounds of formula I may be incorporated e.g. in capsules or tablets with pharmaceutically 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 AWA .W4~o ~<*1~A~AAC 7 7 agents, such as sucrose; flavoring agents, such as peppermint. 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 0. having oleaginous, adsorbable, water soluble and emulsion- S 10 -type bases, such as lanolin and polyethylene glycols.
Topical dosage forms also comprise gels, lotions, powders 1' and aerosols.
0 *i Lotions, i.e. liquid preparations varying from simple 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 incorporate the active ingredient in a vehicle made up of water, alcohol or glycerin. Gels 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 P. polymethylene, and neutralized to a proper gel consistency 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 administration and of a topical cream: -8 Example A Compound E Butylated hydroxytoluene Butylated hydroxyanisole Fractionated coconut oil mg/capsule 0.0001-0.010 0.016 0,016 160.0 Exanmle B 4 40 44 4 444 q 44 444, '$444' 4 4 4~ 4 4 4 44, 4 a wa a 4 4
I
44,4 4 444 o 4 #4 4 44 a a 4 ~a4 4 4; 4 444 44494 a Compound E Cetyl alcohol Stearyl alcohol Sorbitan monostearate Glyceryl monostearate and polyoxyethylene glycol stearate Polysorbate 60 Mineral oil Propylene glycol Propylparaben Butylated hydroxyanisole Sorbitol solution Edetate disodium 25 Methylparaben Distilled water mg/g of cream 0.001-1.0 0 0.05 0.01 0. 18 q.s. to 100 g
Claims (8)
1. A method of treating sebaceous gland diseases in a patient requiring or desiring such treatment, comprising administering to said patient an effective amount of a compound of formula A C(R") 3 YOH C(R")3 H I R wherein R is H or OH, A is -CH=CH- with E-configuration or -CH 2 CH 2 and R" is H or, where A is R" may also be deuterium or of a pharmaceutical composition containing said compound together with a pharmaceutically effective carrier, diluent, excipient and/or adjuvant.
2. A method according to claim 1, wherein in the compound of formula I according to claim 1, R is H or OH, A is and R" is deuterium.
3. A method according to claim 1 or claim 2, wherein the compound or composition is administered in a daily dosage individually determined by the attending physician. 15
4. A method according to any one of claims 1 to 3, wherein said disease is seborrheic dermatitis.
A method according to any one of claims 1 to 3, wherein said disease s.i acne.
6. A compound of formula I CD 3 j V wherein R is H or OH.
7. A dehydrocholecalciferol derivative substantially as hereinbefore described ILibUl00036:JOC t of 3 I r;F1 iO with reference to Compounds G and H of the Examples.
8. A pharmaceutical composition comprising an t, active amount of one or more compounds according to claim 6 or claim 7 and a pharmaceutically acceptable excipient, diluent, carrier and/or adjuvant. Dated 2 February, 1993 F.Hoffmann-La Roche AG Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON i N I 1 t 1% a 0 0e ILibU100036:JOC
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US35371689A | 1989-05-18 | 1989-05-18 | |
US353716 | 1989-05-18 |
Publications (2)
Publication Number | Publication Date |
---|---|
AU5516590A AU5516590A (en) | 1990-11-22 |
AU636609B2 true AU636609B2 (en) | 1993-05-06 |
Family
ID=23390270
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU55165/90A Ceased AU636609B2 (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 |
ES2196476T3 (en) * | 1997-05-02 | 2003-12-16 | Duphar Int Res | A METHOD OF PREPARING COMPOUNDS OF 16-DEHYDRO-VITAMIN D. |
US9221753B2 (en) * | 2004-02-03 | 2015-12-29 | Chugai Seiyaku Kabushiki Kaisha | Process for the synthesis of vitamin D compounds and intermediates for the synthesis of the compounds |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2864389A (en) * | 1988-01-20 | 1989-07-20 | F. Hoffmann-La Roche Ag | Didehydro vitamin d3 derivatives |
AU622139B2 (en) * | 1988-01-20 | 1992-04-02 | F. Hoffmann-La Roche Ag | 16-dehydro-vitamin d3-derivatives |
Family Cites Families (3)
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 |
-
1990
- 1990-05-14 DK DK90109032.4T patent/DK0398217T3/en active
- 1990-05-14 AT AT90109032T patent/ATE99942T1/en not_active IP Right Cessation
- 1990-05-14 DE DE90109032T patent/DE69005897D1/en not_active Expired - Fee Related
- 1990-05-14 EP EP90109032A patent/EP0398217B1/en not_active Expired - Lifetime
- 1990-05-16 NZ NZ233704A patent/NZ233704A/en unknown
- 1990-05-16 ZA ZA903758A patent/ZA903758B/en unknown
- 1990-05-17 AU AU55165/90A patent/AU636609B2/en not_active Ceased
- 1990-05-17 IE IE178090A patent/IE64186B1/en unknown
- 1990-05-17 CA CA002016985A patent/CA2016985C/en not_active Expired - Lifetime
- 1990-05-17 JP JP2128107A patent/JPH0686381B2/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2864389A (en) * | 1988-01-20 | 1989-07-20 | F. Hoffmann-La Roche Ag | Didehydro vitamin d3 derivatives |
AU622139B2 (en) * | 1988-01-20 | 1992-04-02 | F. Hoffmann-La Roche Ag | 16-dehydro-vitamin d3-derivatives |
Also Published As
Publication number | Publication date |
---|---|
EP0398217A1 (en) | 1990-11-22 |
CA2016985A1 (en) | 1990-11-18 |
AU5516590A (en) | 1990-11-22 |
JPH0686381B2 (en) | 1994-11-02 |
DK0398217T3 (en) | 1994-02-14 |
EP0398217B1 (en) | 1994-01-12 |
CA2016985C (en) | 2001-03-27 |
ATE99942T1 (en) | 1994-01-15 |
DE69005897D1 (en) | 1994-02-24 |
IE64186B1 (en) | 1995-07-12 |
JPH0317019A (en) | 1991-01-25 |
IE901780L (en) | 1990-11-18 |
NZ233704A (en) | 1992-11-25 |
ZA903758B (en) | 1992-01-29 |
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