WO1994004149A1

WO1994004149A1 - Use of macrolide compounds for the treatment of skin diseases

Info

Publication number: WO1994004149A1
Application number: PCT/GB1993/001770
Authority: WO
Inventors: Robert Victor Bundick
Original assignee: Fisons Ltd
Current assignee: Fisons Ltd
Priority date: 1992-08-25
Filing date: 1993-08-20
Publication date: 1994-03-03
Anticipated expiration: 1995-02-25
Also published as: ZA936136B; AU4728893A; GB9218597D0; IL106764A0; MX9305151A

Abstract

There is provided the use of a compound of formula (I), wherein R?1 and R2¿ independently represent H or OH, or they may together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R3 represents methyl optionally substituted by -CO¿2?H; ethyl optionally substituted by O, OH or -CO2H; propyl optionally substituted by OH or O; or allyl optionally substituted by OH; R?4¿ represents H; R?5 and R6¿ together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R7 represents O or (H, R7a), where R7a represents H or OH; R?8 and R9¿ 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 R5; R7a and R8; and R3, R4¿ and Y may form various rings together with the carbon atoms to which they are attached; with certain provisos; and pharmaceutically acceptable derivatives thereof; in the manufacture of a medicament for the treatment of inflammatory or hyperproliferative skin diseases or of cutaneous manifestations of immunologically-mediated illnesses.

Description

USE OF MACROLIDE COMPOUNDS FOR THE TREATMENT OF SKIN DISEASES

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 (to Fujisawa Pharmaceutical Co Ltd) 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 (to Fisons pic) 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 (to Merck & Co Inc) 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 (to Merck & Co Inc) 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 (to Sandoz Limited) 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 (to Merck & Co Inc) disclose com¬ pounds described as antagonists of immunosuppressant macrolides of the FR-900506 type.

International Patent Application No WO 91/04025 (to Fisons pic) discloses inter alia the use of macrocyclic compounds related to FR-900506 in which the C20 position is substituted by OH and/or the C17 alkyl or alkenyl substituent is substituted by O. OH or CO₂H and/or the C16 position is substituted with (H.OH) in the treatment of immunodepression or a condition involving immunodepression. European Patent Application 530888 and its equivalent US Patent N° 5.189.042 (to Merck & Co Inc, both published after the priority date of this application) disclose macrocyclic compounds related to FR-900506 in which the C20 position is oxidized or fluorinated. The compounds are indicated inter alia in the treatment of certain skin diseases.

Surprisingly, it has now been found that macrocyclic compounds of the types disclosed in WO 91/04025, EP 403242 and 463690 are efficacious in the treatment of inflammatory and hyperproliferative skin diseases and of cutaneous manifestations of immunologically- mediated illnesses.

Thus, according to the present invention, there is provided the use of a compound of formula I.

wherein

R¹ and R² independently represent H or OH, or they may together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R³ 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: R⁴ represents H:

R⁵ and R^b together represent a second carbon-carbon bond between the carbon atoms to which they are attached:

R⁷ represents O or (H,R^7a), where R^7a represents H or OH: R⁸ and R⁹ independently represent OH or OCH₃;

X and Y independently represent O or (H,OH); and n represents 1 or 2; in addition to their significances above:

R¹ and R⁵ may together represent an oxygen atom, in which case R⁶ and R^7a together represent a second carbon-carbon bond between the carbon atoms to which they are attached;

R^7a and R⁸ may together represent an oxygen atom: and

R\ R⁴ 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 R² represents H; R³ represents methyl, ethyl, propyl or allyl; R⁵ and R⁶ together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R⁸ represents OCH₃; Y represents O; and R⁷ represents (H,H); provided that: a) when R¹ represents OH; R² represents H; R⁵ and R⁶ together represent a second carbon-carbon bond between the carbon atoms to which they are attached: R⁷ represents (H,H); R⁹ represents OCH₃; X and Y each represent O; and n represents

2; then R³ does not represent 2-oxopropyl, 2,3-dihydroxypropyl or ethanalyl; b) when R¹ represents OH; R² represents H; R^s and R⁶ together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R⁷ represents (H,OH); R⁹ represents OCH₃; X and Y each represent O; and n represents 2; then R³ does not represent allyl or l-hydroxyprop-2-enyl; c) when R¹ represents OH; R² represents H; R⁵ and R⁶ together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R⁷ represents (H,H); R⁹ represents OCH₃; X and Y each represent (H.OH); and n represents 2: then R³ does not represent allyl; d) when R¹ and R² 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 between the carbon atoms to which they are attached: R⁷ represents (H,H); R⁹ represents OCH₃; X represents O; Y represents (H.OH): and n represents 2; then R³ does not represent allyl; and e) when R¹ represents OH; R² represents H; R⁵ and R⁶ together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R⁷ represents (H,H); R⁹ represents OCH₃; X represents (H,OH); Y represents O; and n represents 2: then R³ does not represent ethanalyl; and pharmaceutically acceptable derivatives thereof; in the manufacture of a medicament for the treatment of inflammatory or hyper- proliferative skin diseases or of cutaneous manifestations of immunologically-mediated illnesses.

The compounds of formula I and their pharmaceutically acceptable derivatives will be referred to together as 'the compounds of the invention' herein.

In this application, the term "immunologically-mediated illnesses" includes autoimmune diseases.

Pharmaceutically acceptable derivatives of compounds of formula I include 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) and salts (preferably alkali metal salts) of any carboxylic acid groups which may be present; and esters (in which the acid moiety preferably contains from 1 to 6 carbon atoms) of any OH groups which may be present. 5

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.

wherein

R^3b represents ethyl or allyl; R⁷- represents (H,H) or O;

R^8b and R^9b independently represent OH or OCH₃; and

Y^b represents O or (H,OH); but excluding compounds in which together R^71* represents (H,H), R^8b represents OCH₃ 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[22.3.1.0⁴-⁹]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).

According to a second aspect of the invention, there is provided 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.

Turning now to systemic administration, 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. Thus, according to a third aspect of the present invention, there is provided 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. In particular, 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,

wherein R^1'9, n, X and Y are as defined above.

The invention is illustrated by the following example. Example A

17-Allyl-l,14,16-trihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23.25- dimethoxy- 13, 19,21, 27-tetramethyl-11.28-dioxa-4-azatricyclo[22.3.1.0^4,9]octacos-18-ene- 2,3,10-trione was tested in the TPA-induced cutaneous inflammatory response screen described above, and found to inhibit the inflammatory response as shown in the following table:

Claims

Claims:

The use of a compound of formula I,

wherein

R¹ and R² independently represent H or OH, or they may together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R³ represents methyl optionally substituted by -C0₂H; ethyl optionally substituted by O,

OH or -CO,H; propyl optionally substituted by OH or O: or allyl optionally substituted by OH;

R⁴ represents H;

R^s and R⁶ together represent a second carbon-carbon bond between the carbon atoms to which they are attached;

R⁷ represents O or (H,R^7a), where R^7a represents H or OH;

R⁸ and R⁹ independently represent OH or OCH₃;

X and Y independently represent O or (H.OH); and n represents 1 or 2: in addition to their significances above: R¹ and R⁵ may together represent an oxygen atom, in which case R" and R'^a together represent a second carbon-carbon bond between the carbon atoms to which they are attached;

R^7a and R⁸ may together represent an oxygen atom: and R³. R⁴ 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 R² represents H; R³ represents methyl, ethyl, propyl or allyl; R^s and R⁶ together represent a second carbon-carbon bond between the carbon atoms to which they are attached: R⁸ represents OCH₃; Y represents O; and R⁷ represents (H,H); provided that: a) when R¹ represents OH: R² represents H; R⁵ and R⁶ together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R⁷ represents (H,H); R⁹ represents OCH₃; X and Y each represent O; and n represents s 2; then R³ does not represent 2-oxopropyl, 2,3-dihydroxypropyl or ethanalyl; b) when R¹ represents OH; R² represents H; R⁵ and R⁶ together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R⁷ represents (H.OH); R⁹ represents OCH₃; X and Y each represent O; and n represents 2; then R³ does not represent allyl or l-hydroxyprop-2-enyl; o c) when R¹ represents OH; R² represents H; R⁵ and R⁶ together represent a second carbon-carbon bond between the carbon atoms to which they are attached: R⁷ represents (H,H); R⁹ represents OCH₃; X and Y each represent (H.OH); and n represents 2; then R³ does not represent allyl; d) when R¹ and R² together represent a second carbon-carbon bond between the 5 carbon atoms to which they are attached; R⁵ and R⁶ together represent a second carbon-carbon bond between the carbon atoms to which they are attached; R⁷ represents (H,H); R⁹ represents OCH₃; X represents O; Y represents (H.OH); and n represents 2; then R³ does not represent allyl; and e) when R¹ represents OH: R² represents H; R⁵ and R⁶ together represent a 0 second carbon-carbon bond between the carbon atoms to which they are attached; R⁷ represents (H.H); R⁹ represents OCH₃: X represents (H.OH); Y represents O; and n represents 2: then R³ does not represent ethanalyl; and pharmaceutically acceDtable derivatives thereof: in the manufacture of a medicament for the treatment of inflammatory or hyperproiiferative skin diseases or of cutaneous manifestations of immunologically- mediated illnesses.

2. The use as claimed in claim 1, wherein the compound of formula I is a compound of formula lb.

wherein

R^3b represents ethyl or allyl;

R^ represents (H,H) or O;

R^8b and R^9b independently represent OH or OCH₃; and

Y^b represents O or (H,OH); but excluding compounds in which together R⁷- represents (H,H), R^8b represents OCH₃ and Y^b represents O; and pharmaceutically acceptable derivatives thereof.

3. The use as claimed in claim 1 or claim 2. wherein the compound of formula I is 17-allyl-l,14,16-trihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-l-methylvinyl]-23,25- dimethoxy-13,19,21.27-tetramethyl-11.28-dioxa-4-azatricyclo[22.3.1.0⁴-⁹]octacos-18-ene- 2,3,10-trione. or a pharmaceutically acceptable derivative thereof.

4-. The use as claimed in any one of claims 1 to 5. wherein the disease is psoriasis.

5. A pharmaceutical formulation including a compound of formula I, as defined in any one of claims 1 to 3. or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which is adapted for topical administration to the skin.

6. A formulation as claimed in claim 5, which is a lotion, gel or cream.

7. 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 formula I, as defined in any one of claims 1 to 5, or a pharmaceutically acceptable derivative thereof, to a patient.

8. The method as claimed in claim 7, wherein the compound of formula I, or a pharmaceutically acceptable derivative thereof, is applied topically to the skin.

9. The method as claimed in claim 7, wherein the compound of formula I, or a pharmaceutically acceptable derivative thereof, is administered orally to the gastro¬ intestinal tract.

10. The method as claimed in claim 7, wherein the disease is psoriasis.