[go: up one dir, main page]

WO1994004149A1 - Utilisation de composes de la classe des macrolides pour le traitement de maladies de la peau - Google Patents

Utilisation de composes de la classe des macrolides pour le traitement de maladies de la peau Download PDF

Info

Publication number
WO1994004149A1
WO1994004149A1 PCT/GB1993/001770 GB9301770W WO9404149A1 WO 1994004149 A1 WO1994004149 A1 WO 1994004149A1 GB 9301770 W GB9301770 W GB 9301770W WO 9404149 A1 WO9404149 A1 WO 9404149A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbon
represent
attached
carbon atoms
och
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
Application number
PCT/GB1993/001770
Other languages
English (en)
Inventor
Robert Victor Bundick
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fisons Ltd
Original Assignee
Fisons Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Fisons Ltd filed Critical Fisons Ltd
Priority to AU47288/93A priority Critical patent/AU4728893A/en
Publication of WO1994004149A1 publication Critical patent/WO1994004149A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

Definitions

  • This invention relates to a novel treatment of certain skin diseases utilizing macrocyclic compounds, and to pharmaceutical formulations including such compounds.
  • European Patent Application 184162 discloses several macrolides (numbered FR-900506, FR-900520, FR-900523 and FR-900525) and derivatives thereof which are isolated from microorganisms belonging to the genus Streptomyces. The macrolides are indicated as immunosuppressive agents.
  • European Patent Application 323042 discloses many macrolides which may be derived from those disclosed in European Patent Application 184162. Again, the compounds are primarily indicated as immunosuppressive agents.
  • European Patent Applications 349049. 349061 and 388153 disclose the dihydroxy- cyclohexyl derivatives of FR-900506.
  • FR-900520 and FR-900523 respectively and indicate them primarily as immunosuppressive agents.
  • European Patent Application 405994 discloses a method of converting compounds such as FR-900506 which contain a piperidine ring into their pyrrolidine ring-containing analogues.
  • a number of the above-mentioned documents indicate the compounds disclosed in the treatment of skin diseases.
  • UK Patent Application 2212061 specifically relates to the use of the compounds disclosed in EP 184162 in the treatment of certain skin diseases.
  • European Patent Applications 403242 and 463690 disclose com ⁇ pounds described as antagonists of immunosuppressant macrolides of the FR-900506 type.
  • R 1 and R 2 independently represent H or OH, or they may together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
  • R 3 represents methyl optionally substituted by -CO : H; ethyl optionally substituted by O.
  • OH or -CO H; propyl optionally substituted by OH or O; or allyl optionally substituted bv OH:
  • R 4 represents H:
  • R 5 and R b together represent a second carbon-carbon bond between the carbon atoms to which they are attached:
  • R 7 represents O or (H,R 7a ), where R 7a represents H or OH: R 8 and R 9 independently represent OH or OCH 3 ;
  • X and Y independently represent O or (H,OH); and n represents 1 or 2; in addition to their significances above:
  • R 1 and R 5 may together represent an oxygen atom, in which case R 6 and R 7a together represent a second carbon-carbon bond between the carbon atoms to which they are attached;
  • R 7a and R 8 may together represent an oxygen atom:
  • R ⁇ R 4 and Y together with the carbon atoms to which they are attached, may represent a methyl-substituted furanyl ring; but excluding compounds in which together R 2 represents H; R 3 represents methyl, ethyl, propyl or allyl; R 5 and R 6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R 8 represents OCH 3 ; Y represents O; and R 7 represents (H,H); provided that: a) when R 1 represents OH; R 2 represents H; R 5 and R 6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached: R 7 represents (H,H); R 9 represents OCH 3 ; X and Y each represent O; and n represents
  • R 3 does not represent 2-oxopropyl, 2,3-dihydroxypropyl or ethanalyl; b) when R 1 represents OH; R 2 represents H; R s and R 6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R 7 represents (H,OH); R 9 represents OCH 3 ; X and Y each represent O; and n represents 2; then R 3 does not represent allyl or l-hydroxyprop-2-enyl; c) when R 1 represents OH; R 2 represents H; R 5 and R 6 together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R 7 represents (H,H); R 9 represents OCH 3 ; X and Y each represent (H.OH); and n represents 2: then R 3 does not represent allyl; d) when R 1 and R 2 together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R and R° together represent a second carbon-carbon bond
  • the term "immunologically-mediated illnesses” includes autoimmune diseases.
  • esters in which the alcohol moiety preferably contains from 1 to 6 carbon atoms
  • amides in which the amine moiety preferably contains from 0 to 6 carbon atoms
  • salts preferably alkali metal salts
  • esters in which the acid moiety preferably contains from 1 to 6 carbon atoms of any OH groups which may be present.
  • the compounds of the invention may be prepared by the methods given in the documents mentioned above, particularly WO 91/04025, EP 403242, EP 463690 and EP 405994 as appropriate.
  • the compounds may also be prepared by total synthesis by modification of the method described by Askin et al. J Am Chem Soc, 1989, vol 111(11), o pll57.
  • a preferred group of compounds of formula I are the compounds of formula lb.
  • R 3b represents ethyl or allyl
  • R 7 - represents (H,H) or O
  • R 8b and R 9b independently represent OH or OCH 3 ;
  • Y b represents O or (H,OH); but excluding compounds in which together R 71* represents (H,H), R 8b represents OCH 3 and Y b represents O; and pharmaceutically acceptable derivatives thereof.
  • a compound of formula I (and formula lb) of particular interest is 17-allyl- l,14, 16-trihydroxy- 12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25- dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0 4 - 9 ]octacos-18-ene- 2,3,10-trione (first disclosed in WO 91/04025, Example 13).
  • Skin diseases which may be mentioned include: psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis. Lichen planus. Pemphigus, bullous Pemphigoid. Epidermolysis bullosa, urticaria, angioedemas. vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus and Alopecia areata. Psoriasis is of particular interest.
  • the compounds of the invention may be screened for their potential anti-psoriasis efficacy in the TPA-induced cutaneous inflammatory response screen described by R J Griffiths, B E Wood, S Li and A Blackham in 'Effects of ciclosporin and protein synthesis inhibitors on cutaneous inflammation in mouse skin'. Skin Pharmacology, 2. 30- 37, 1989.
  • Administration of the compound of the invention may be topical (for example by application to the skin), or systemic (for example by oral administration to the gastro ⁇ intestinal tract).
  • a pharmaceutical formulation including a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which is adapted for topical administration to the skin.
  • the formulation may be in the form of a lotion, gel or cream, and preferably contains the compound of the invention in a concentration of 0.003-3% by weight.
  • Such formulations may be prepared by the methods described in European Patent Appli ⁇ cation 423714.
  • the compound of the invention may be formulated together with known adjuvants, diluents or carriers using conventional techniques to produce tablets or capsules for oral administration to the gastrointestinal tract.
  • Suitable doses for such oral administration are in the range from 0.003 to 0.3mg.kg “1 .day "1 , for example 0.03mg.kg 'I .day '1 .
  • Such formulations may be prepared by the methods described by T Hondo et al. Transplantation Proceedings, 1987, XD Supp 6, 17-22.
  • the dosage to be administered will of course vary with the particular compound of the invention, the condition to be treated and with its severity.
  • the compound of the invention may be administered as divided doses from 1 to 6. and preferably 2 to 4, times per day. Each dose may comprise 1 or more unit doses.
  • a method of treatment of an inflammatory or hyperproiiferative skin disease or of a cutaneous manifestation of an immunologically-mediated illness which comprises administration of a therapeutically effective amount of a compound of the invention to a patient.
  • the method of treatment according to the invention has the advantage that the compounds of the invention are more efficacious, less toxic, are longer acting, have a broader range of activity, are more potent, produce fewer side effects, are more easily absorbed or have other more useful pharmacological properties, than compounds previously indicated in the treatment of inflammatory or hyperproiiferative skin diseases or of cutaneous manifestations of immunologically-mediated illnesses.
  • the compounds of the invention have a less pronounced immunosuppressive effect than the compounds indicated in GB 2212061, and hence are more selective.
  • the invention relates to all stereoisomers of the compounds of the invention.
  • the preferred stereochemistry of certain carbon atoms is indicated in formula Ia,
  • R 1'9 , n, X and Y are as defined above.
  • Example A The invention is illustrated by the following example.
  • Example A The invention is illustrated by the following example.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne l'utilisation d'un composé de la formule (I). Dans cette formule, R1 et R2 représentent d'une manière indépendante H ou OH ou ils peuvent représenter ensemble une seconde liaison carbone-carbone entre les atomes de carbone auxquels ils sont fixés; R3 représente un méthyle, éventuellement substitué par -CO¿2?H; un éthyle éventuellement substitué par O, OH ou -CO2H; un propyle éventuellement substitué par OH ou O; ou un allyle éventuellement substitué par OH; R?4¿ représente H; R5 et R6 représentent ensemble une seconde liaison carbone - carbone entre les atomes de carbone auxquels ils sont fixés; R7 représente O ou (H, R?7a), où R7a¿ représente H ou OH; R8 et R9 représentent indépendamment OH ou OCH¿3?; X et Y représentent indépendamment O ou (H, OH); et n représente 1 ou 2; en plus de la signification donnée ci-dessus, R?1 et R5; R7a et R8; et R3, R4¿ et Y peuvent former ensemble différents cycles avec les atomes de carbone auxquels ils ont fixés, pourvu que certaines conditions soient satisfaites. L'invention concerne également les dérivés de ces produits acceptables sur le plan pharmaceutique, ainsi que leur utilisation pour la fabrication d'un médicament pour le traitement de maladies inflammatoires ou hyperprolifératives de la peau, ou de manifestations cutanées de maladies à médiation immunologique.
PCT/GB1993/001770 1992-08-25 1993-08-20 Utilisation de composes de la classe des macrolides pour le traitement de maladies de la peau Ceased WO1994004149A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU47288/93A AU4728893A (en) 1992-08-25 1993-08-20 Use of macrolide compounds for the treatment of skin diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9218597.4 1992-08-25
GB929218597A GB9218597D0 (en) 1992-08-25 1992-08-25 Novel method of treatment

Publications (1)

Publication Number Publication Date
WO1994004149A1 true WO1994004149A1 (fr) 1994-03-03

Family

ID=10721299

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/001770 Ceased WO1994004149A1 (fr) 1992-08-25 1993-08-20 Utilisation de composes de la classe des macrolides pour le traitement de maladies de la peau

Country Status (6)

Country Link
AU (1) AU4728893A (fr)
GB (1) GB9218597D0 (fr)
IL (1) IL106764A0 (fr)
MX (1) MX9305151A (fr)
WO (1) WO1994004149A1 (fr)
ZA (1) ZA936136B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10259827B2 (en) 2016-11-10 2019-04-16 Novartis Ag BMP potentiators
EP4161510A4 (fr) * 2020-06-09 2024-08-07 Uniquest Pty Ltd Composé pour la prévention ou le traitement d'un cancer de la peau ou d'un précancer de la peau

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0315978A2 (fr) * 1987-11-09 1989-05-17 Sandoz Ag Utilisation de dérivés de 11,28-dioxa-4-azatricyclo[22.3.1.0 4,9]octacos-18-ène et compositions pharmaceutiques les contenant
EP0323042A1 (fr) * 1987-12-09 1989-07-05 FISONS plc Procédé pour macrolides
WO1991004025A1 (fr) * 1989-09-14 1991-04-04 Fisons Plc Nouveaux composes macrocycliques et nouvelle methode de traitement

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0315978A2 (fr) * 1987-11-09 1989-05-17 Sandoz Ag Utilisation de dérivés de 11,28-dioxa-4-azatricyclo[22.3.1.0 4,9]octacos-18-ène et compositions pharmaceutiques les contenant
EP0323042A1 (fr) * 1987-12-09 1989-07-05 FISONS plc Procédé pour macrolides
WO1991004025A1 (fr) * 1989-09-14 1991-04-04 Fisons Plc Nouveaux composes macrocycliques et nouvelle methode de traitement

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10259827B2 (en) 2016-11-10 2019-04-16 Novartis Ag BMP potentiators
EP4161510A4 (fr) * 2020-06-09 2024-08-07 Uniquest Pty Ltd Composé pour la prévention ou le traitement d'un cancer de la peau ou d'un précancer de la peau

Also Published As

Publication number Publication date
ZA936136B (en) 1994-02-21
IL106764A0 (en) 1993-12-08
AU4728893A (en) 1994-03-15
GB9218597D0 (en) 1992-10-14
MX9305151A (es) 1994-05-31

Similar Documents

Publication Publication Date Title
US6951841B2 (en) Pharmaceutical compositions of macrolides or cyclosporine with a polyethoxylated saturated hydroxy-fatty acid
US7741338B2 (en) Macrolides
EP0754040B1 (fr) Derives de la rapamycine
JP3396888B2 (ja) 医薬組成物
JPH05306289A (ja) ラパマイシン二量体
US5750534A (en) Nalbuphine esters having long acting analgesic action and method of use
AU2003258607B2 (en) Topical anhydrous and ethanol-free ascomycin compositions
EP0615756B1 (fr) Esters de nalbuphine, et compositions pharmaceutiques à action prolongée les contenant
JPH03118385A (ja) マクロ環状化合物
WO1994004149A1 (fr) Utilisation de composes de la classe des macrolides pour le traitement de maladies de la peau
JP3108192B2 (ja) 免疫抑制剤、抗炎症剤または抗真菌剤用ラパマイシンの還元生成物
WO1994004148A1 (fr) Utilisation de composes de la classe des macrolides dans le traitement de maladies entrainant une obstruction reversible des voies aeriennes
WO1993014771A1 (fr) Composes macrocycliques servant au traitement prophylactique du sida
GB2327610A (en) Stabilisation of Macrolide Compositions
WO1993016083A1 (fr) Composes macrocycliques et utilisation de ces derniers en tant que produits pharmaceutiques
JPH06501923A (ja) トリシクロ化合物及びその製法並びにその物を含む医薬組成物
WO1994005685A1 (fr) Composes macrocycliques utilises en therapie
KR100304327B1 (ko) 라파마이신의카밤산염및이를포함하는약제학적조성물
HK1089656A (en) Pharmaceutical compositions of macrolides or cyclosporine with a polyethoxylated saturated hydroxy-fatty acid
HK1146246A (en) Stabilisation of macrolides
HK1102910A (en) Stabilisation of macrolides

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP KR NO NZ

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase