GB2313059A - Pyrrolyl-containing compositions for the topical treatment of skin disorders - Google Patents

Pyrrolyl-containing compositions for the topical treatment of skin disorders Download PDF

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Publication number
GB2313059A
GB2313059A GB9717156A GB9717156A GB2313059A GB 2313059 A GB2313059 A GB 2313059A GB 9717156 A GB9717156 A GB 9717156A GB 9717156 A GB9717156 A GB 9717156A GB 2313059 A GB2313059 A GB 2313059A
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United Kingdom
Prior art keywords
compound
pityriasis
dermatoses
cis
responsive
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.)
Granted
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GB9717156A
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GB9717156D0 (en
GB2313059B (en
Inventor
Michael Goodman
James Ferguson
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Bioglan Ireland R&D Ltd
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Bioglan Ireland R&D Ltd
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Priority claimed from GB939306473A external-priority patent/GB9306473D0/en
Application filed by Bioglan Ireland R&D Ltd filed Critical Bioglan Ireland R&D Ltd
Priority to GB9717156A priority Critical patent/GB2313059B/en
Publication of GB9717156D0 publication Critical patent/GB9717156D0/en
Publication of GB2313059A publication Critical patent/GB2313059A/en
Application granted granted Critical
Publication of GB2313059B publication Critical patent/GB2313059B/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • 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
    • A61Q7/00—Preparations for affecting hair growth

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

Abstract

The present invention relates to compounds of general formula I:- Q-R-X (I) wherein Q is a substituted or unsubstituted pyrrolyl group, R is CR 1 2 -CR 2 2 , (cis)CR 1 = CR 2 , or (trans)CR 1 =CR 2 , X is COOR 3 or NR 1 R 4 , and R 1 -R 4 are each, independently, H, or an alkyl or an aryl group and to pharmaceutically acceptable salts thereof, for use in the topical treatment of skin conditions which are responsive to ultraviolet (UV) radiation.

Description

PHARMACEUTICALLY USEFUL PYRROLYL DERIVATIVES DESCRIPTION The present invention relates to compounds of general formula I: Q-R-X (I) wherein Q is a substituted or unsubstituted pyrrolyl group, R is CR12-CR22, (cis)CR1 = CR2, or (trans)CRl=CR2, X is COOR3 or NR1R4 and R1-R4 are each, independently, H, or an alkyl or an aryl group and to pharmaceutically acceptable salts thereof. The invention also relates to the use of such compounds in the topical treatment of skin conditions which are responsive to ultraviolet (UV) radiation.
Trans-urocanic acid (UCA) is a naturally occurring compound found in the upper layers of the epidermis, where it is synthesized through deamination of histidine by histidase. When the skin is irradiated with ultraviolet light, up to 60 or 70W of the trans-UCA present is converted into the cis-isomer and it is thought that cis-UCA, once so generated, functions as a mediator in both systemic and local UV induced immune system suppression. See the review article by M. Norval et al. in Photochemistry and Photobiology Vol. 50. No. 2, pp 267-275, 1989 (1).
Support for the proposition that cis-UCA is a mediator in W induced suppression of the immune system is provided by the work reported by M. Norval et al. in Photochemistry and Photobiology Vol. 49. No. 5, pp 633639, 1989 and that of V.E. Reeve et al., reported in Photodermatol Photoimmunol Photoreed 1991: 8: pp 176 180. The former authors found that cis-UCA was able to induce suppression of normal delayed type hypersensitivity response to herepes s i m p 1 e x virus type 1 in mice and the latter found that cis-UCA, generated by applying trans-UCA (in a cosmetic cream) to murine skin and then irradiating the treated skin, systemically suppressed normal c o n t a c t hyper-sensitivity. Reeve et al. suggested that this activity is potentially harmful, since it could result in tumour development and, therefore, concluded that urocanic acid was potentially hazardous and should not be used as a cosmetic ingredient. Indeed, Reeve et al., in Photochemistry and Photobiology Vol. 49. No.
4. pp 459-464. 1989., reported that topically applied trans -UCA significantly increased the tumour load induced in hairless mice, on exposure to Erythema inducing doses of W light or sunlight.
Thus, rather than being confirmed as therapeutically useful, investigation of their metabolic roles has led to the removal of trans-UCA from various commercially available cosmetic creams (see Concar in the New Scientist, 16th May, 1992), to obviate the risk of it being transformed into the apparently harmful cis-isomer, and to cis-UCA being considered of potential use only in the treatment of serious or life-threatening conditions, such as those involving transplant surgery, etc. For example, cis-UCA has been suggested as a possible immunosuppressive agent for use in transplant surgery, particularly in skin grafting.
However, contrary to the indications discussed above, it has now been found that certain UCA analogues can be therapeutically useful. Accordingly, the present invention provides a compound of general formula I, or a pharmaceutically acceptable salt thereof: Q-R-X (I) wherein Q, R and X are as hereinbefore defined, for use in a topical treatment of a skin condition which is responsive to Irradiation and selected from polymorphic light eruption, actinic prurigo, solar urticaria, acne vulgaris, alopecia areata, dermatitis herpetiformis, eosinophilic pustular folliculitis, erythrokeratoderma (symmetrical and progressive), chronic lichenoid GVH disease, granuloma annulare, histiocytosis ichthyosis linearis circumflexa, lichen planus, pityriasis lichenoides, pityriasis rosea, pityriasis rubra pilaris, subcorneal pustular dermatoses, transient acantholytic dermatoses, psoriasis and atopic eczema. The invention, preferably, can relate to just one or a selection of the aforementioned conditions.
In a third aspect, the invention provides the use of a compound of general formula (I), as hereinbefore defined, for the manufacture of a medicament for use in the treatment of any one, a selection, or all of the conditions defined, or listed above.
In a further aspect, the present invention provides a pharmaceutical composition, comprising a compound of general formula (I), as hereinbefore defined, in admixture with a pharmaceutically acceptable excipient or carrier and suitable for topical use in treating a condition as hereinbefore defined or listed above.
In embodiments of any aspect of the invention, Q, in general formula (I), can be substituted with F, Cl, Br or -CH3 but, preferably, is unsubstituted; R1-R4 each, independently, can be H, a lower alkyl group (preferably Cl-C4) or a phenyl group but, preferably, are H; and R, preferably, is (cis)CRl=CR2.
Preferred pharmaceutical compositions, in accordance with the present invention, comprise ointments, gels, aerosols, wipes, creams, lotions or emulsions which include a compound of general formula I, in admixture with a suitable carrier, mixture of carriers or emulsion thereof.
Methods of synthesizing compounds of formula I are set out in M. Norval et al., Photochemistry and Photobiology Vol. 49. No. 5. pp 633-639. 1989.
Pharmaceutical compositions, such as those set out in the following examples, may be prepared by incorporating a compound of formula I into a conventional pharmaceutical cream or other suitable base, using conventional techniques known in the art.
The following examples are provided by way of illustration only.
Example 1 Gel Composition.
100g of a gel composition, suitable for topical application to the skin, were prepared from the following quantities of the following substances: cis-UCA 1 .Og Hydroxyethyl cellulose 2.0g NIPASEPT (RTM) Sodium 0.15g Glycerol 10g Water to 100g.
The hydroxyethyl cellulose used was Cellosize QP52, OOOH and was employed as a viscosity enhancer, as well as to provide the composition with the required gel characteristics.
The cis-UCA was prepared from trans-UCA by irradiating a thinly spread solution of l.Og of trans-UCA, in dimethyl sulphoxide (lOmg/ml), with two Phillips TL 20w/l UV lamps for three hours. The conversion rate of trans-UCA to cis-UCA was approximately 70k and, therefore, the cis-UCA used contained up to about 30k trans-UCA. After irradiation, the remaining solvent was removed by evaporation and the cis UCA was dissolved in a portion of the water. The remaining components were then mixed into the resulting solution and the rest of the water was added to form the final gel.
Example 2 Cis-UCA, formed by the irradiation method set out in Example 1, was mixed into a jelly formed from 50% white soft paraffin and 50k liquid paraffin at a concentration of about 2% w/w. The resulting composition was suitable for topical application to the skin.
Example 3 Non-aqueous Spray.
Non-aqueous sprays in accordance with the invention can be prepared using the following materials in the proportions set out below: % w/v cis-UCA 0.1-5 isopropyl isostearate 10-40 cyclomethicone 10-40 AZONE (RTM) 0-20 oil (preferably coconut) to 100 The preferred composition for such a spray is 2% cis UCA, 30k isopropyl isostearate, 30% cyclomethicone, 5% azone and 33k coconut oil (all %/w/v).
Example 4 Gel composition.
Further gels in accordance with the invention can be prepared using the following materials in the proportions set out below: % w/w cis-UCA 0.1-10 Sodium carboxymethy cellulose 1.5-2.5 Sorbic acid 0.75 Propylene glycol 2.0-25 Buffering agent 0.01-1 Purified Water to 100 The preferred composition for such a gel is 5% cis-UCA, 2% sodium carboxymethyl cellulose, 0. 75% sorbic acid 10% propylene glycol, 0. 1% buffering agent and purified water to 100% (all %w/w).
Example 5 Cream Composition.
Creams in accordance with the invention can be prepared using the following materials in the proportions set out below: cis-UCA 0.1-10 Cosmowax 10-25 Oleyl Alcohol 0.1-10 Oleic Acid 0.1-10 Liquid Paraffin 5-25 Polysorbate 20 0.1-5 PHENONIP (RTM) 0.1-1 Buffering Agent 0.01-1 Sorbic Acid 0.075 Purified Water to 100 The preferred composition for such a cream is 5% cis-UCA, 15% cosmowax, 3k oleyl alcohol, 2% olecic acid, 15% liquid paraffin, 1% polysorbate 20, 0.5k phenonip, 0.1% buffering agent, 0.075% sorbic acid and water to 100%.
Example 6 Paint Composition.
Paints in accordance with the invention can be prepared using the following materials in the proportions set out below: w/v cis-UCA 0.1-10 Purified Water 0-60 Dimethyl Sulphoxide To 100 The preferred composition for such a paint is 5% cis-UCA, 20% purified water and 75 dimethyl sulphoxide.

Claims (11)

1. A compound of general formula I, or a pharmaceutically acceptable salt thereof: Q-R-X (I) wherein Q is a substituted or unsubstituted pyrrolyl group, R is CR12-CR22, (cis)CR1=CR2, or (trans)-CR1=CR2 X is COOR3 or NR1R4, and R1-R4 are each, independently, H, or an alkyl or an aryl group, for use in a topical treatment of a skin condition which is responsive to UV irradiation and selected from polymorphic light eruption, actinic purrigo, solar urticaria, acne vulgaris, alopecia areata, dermatitis herpetiformis, eosinophilic pustular folliculitis, erythrokeratoderma (symmetrical and progressive), chronic lichenoid GVH disease, granuloma annulare, histiocytosis X, ichthyosis linearis circumflexa, lichen planus, pityriasis lichenoides, pityriasis rosea, pityriasis rubra pilaris, subcorneal pustular dermatoses, transient acantholytic dermatoses, psoriasis and atopic eczema.
2. A compound as claimed in claim 1, wherein Q is unsubstituted, or substituted with F, Cl, Br or CH3.
3. A compound as claimed in claim 1 or claim 2, wherein R1-R4 each, independently, are H, a lower alkyl group or a phenyl group.
4. A compound as claimed in any of claims 1-3, wherein R is (cis) CR1 = CR2.
5. A compound as claimed in any of claims 2-4, wherein Q is unsubstituted.
6. A compound as claimed in any of claims 2-5, wherein R1-R4 are each H.
7. A pharmaceutical composition comprising a compound of general formula I, as defined in any of claims 1-6, in admixture with a pharmaceutically acceptable excipient or carrier, for topical use in the treatment of a skin condition which is responsive to W irradiation and selected from polymorphic light eruption, actinic purrigo, solar urticaria, acne vulgaris, alopecia areata, dermatitis herpetiformis, eosinophilic pustular folliculitis, erythrokeratoderma (symmetrical and progressive), chronic lichenoid GVH disease, granuloma annulare, histiocytosis X, ichthyosis linearis circumflexa, lichen planus, pityriasis lichenoides, pityriasis rosea, pityriasis rubra pilaris, subcorneal pustular dermatoses, transient acantholytic dermatoses, psoriasis and atopic eczema.
8. A pharmaceutical composition, as claimed in claim 7, comprising an ointment, gel, aerosol, wipe, cream, lotion or emulsion.
9. Use of a compound of general formula I, as defined in any of claims 1-6, for the manufacture of a medicament for use in a method of topically treating a skin condition which is responsive to Wirradiation and selected from polymorphic light eruption, actinic purrigo, solar urticaria, acne vulgaris, alopecia areata, dermatitis herpetiformis, eosinophilic pustular folliculitis, erythrokeratoderma (symmetrical and progressive), chronic lichenoid GVH disease, granuloma annulare, histiocytosis X, ichthyosis linearis circumflexa, lichen planus, pityriasis lichenoides, pityriasis rosea, pityriasis rubra pilaris, subcorneal pustular dermatoses, transient acantholytic dermatoses, psoriasis and atopic eczema.
10. A use, as claimed in claim 9, wherein the medicament includes a pharmaceutically acceptable excipient or carrier and is suitable for topical use.
11. A use, as claimed in claim 10, wherein the medicament is an ointment, gel, aerosol, wipe, cream, lotion or emulsion.
11. A use, as claimed in claim 10, wherein the medicament is an ointment, gel, aerosol, wipe, cream, lotion or emulsion.
Amendments to the claims have been filed as follows 1. A compound of general formula I, or a pharmaceutically acceptable salt thereof: Q-R-X (I) wherein Q is a substituted or unsubstituted pyrrolyl group, R is CR12-CR22, (cis)CRl=CR2, or (trans)-CRl=CR2, X is COOR3 or NR1R4, and R1-R4 are each, independently, H, or an alkyl or an aryl group, for use in a topical treatment of a skin condition which is responsive to UV irradiation and selected from polymorphic light eruption, actinic purrigo, solar urticaria, acne vulgaris, alopecia areata, dermatitis herpetiformis, eosinophilic pustular folliculitis, erythrokeratoderma (symmetrical and progressive), chronic lichenoid GVH disease, granuloma annulare, histiocytosis X, ichthyosis linearis circumflexa, lichen planus, pityriasis lichenoides, pityriasis rosea, pityriasis rubra pilaris, subcorneal pustular dermatoses, transient acantholytic dermatoses, psoriasis and atopic eczema.
2. A compound as claimed in claim 1, wherein Q is unsubstituted, or substituted with F, Cl, Br or CH.
3. A compound as claimed in claim 1 or claim 2, wherein R1-R4 each, independently, are H, a lower alkyl group or a phenyl group.
4. A compound as claimed in any of claims 1-3, wherein R is (cis) CR1 = CR2.
5. A compound as claimed in any of claims 2-4, wherein Q is unsubstituted.
6. A compound as claimed in any of claims 2-5, wherein R1-R4 are each H.
7. A pharmaceutical composition, comprising a compound as claimed in any of claims 1-6 in admixture with a pharmaceutically acceptable excipient or carrier, for topical use in the treatment of a skin condition which is responsive to W irradiation and selected from polymorphic light eruption, actinic purrigo, solar urticaria, acne vulgaris, alopecia areata, dermatitis herpetiformis, eosinophilic pustular folliculitis, erythrokeratoderma (symmetrical and progressive), chronic lichenoid GVH disease, granuloma annulare, histiocytosis X, ichthyosis linearis circumflexa, lichen planus, pityriasis lichenoides, pityriasis rosea, pityriasis rubra pilaris, subcorneal pustular dermatoses, transient acantholytic dermatoses, psoriasis and atopic eczema.
8. A pharmaceutical composition, as claimed in claim 7, comprising an ointment, gel, aerosol, wipe, cream, lotion or emulsion.
9. Use of a compound as claimed in any of claims 1-6, for the manufacture of a medicament for use in a method of topically treating a skin condition which is responsive to W irradiation and selected from polymorphic light eruption, actinic purrigo, solar urticaria, acne vulgaris, alopecia areata, dermatitis herpetiformis, eosinophilic pustular folliculitis, erythrokeratoderma (symmetrical and progressive), chronic lichenoid GVH disease, granuloma annulare, histiocytosis X, ichthyosis linearis circumflexa, lichen planus, pityriasis lichenoides, pityriasis rosea, pityriasis rubra pilaris, subcorneal pustular dermatoses, transient acantholytic dermatoses, psoriasis and atopic eczema.
10. A use, as claimed in claim 9, wherein the medicament includes a pharmaceutically acceptable excipient or carrier and is suitable for topical use.
GB9717156A 1993-03-29 1994-03-29 Pharmaceutically useful pyrrolyl derivatives Expired - Fee Related GB2313059B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
GB9717156A GB2313059B (en) 1993-03-29 1994-03-29 Pharmaceutically useful pyrrolyl derivatives

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB939306473A GB9306473D0 (en) 1993-03-29 1993-03-29 Pharmaceutically useful compounds
GB9717156A GB2313059B (en) 1993-03-29 1994-03-29 Pharmaceutically useful pyrrolyl derivatives
GB9519866A GB2291594B (en) 1993-03-29 1994-03-29 Pharmaceutically useful furanyl derivatives for topical use

Publications (3)

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GB9717156D0 GB9717156D0 (en) 1997-10-22
GB2313059A true GB2313059A (en) 1997-11-19
GB2313059B GB2313059B (en) 1998-01-21

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GB9717155A Expired - Fee Related GB2313058B (en) 1993-03-29 1994-03-29 Pharmaceutically useful thiopheneyl derivatives
GB9717157A Expired - Fee Related GB2313546B (en) 1993-03-29 1994-03-29 Pharmaceutically useful imidazolyl derivatives
GB9717156A Expired - Fee Related GB2313059B (en) 1993-03-29 1994-03-29 Pharmaceutically useful pyrrolyl derivatives

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GB9717155A Expired - Fee Related GB2313058B (en) 1993-03-29 1994-03-29 Pharmaceutically useful thiopheneyl derivatives
GB9717157A Expired - Fee Related GB2313546B (en) 1993-03-29 1994-03-29 Pharmaceutically useful imidazolyl derivatives

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0342055A2 (en) * 1988-05-13 1989-11-15 Unilever Plc Use of pyroglutamic acid alkyl esters for the manufacture of a medicament for the treatment of ichthyosis
WO1996010013A1 (en) * 1994-09-27 1996-04-04 Ono Pharmaceutical Co., Ltd. Five membered heterocyclic compounds

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL107854C (en) * 1958-04-25
GB2097783B (en) * 1981-04-23 1984-12-12 Dermal Lab Ltd Imidazoles
IN166447B (en) * 1985-11-27 1990-05-12 Ethicon Inc
EP0272704A3 (en) * 1986-12-26 1990-11-22 Sanwa Kagaku Kenkyusho Co., Ltd. Use of pyrazole derivatives in the treatment of immunity diseases and nephropathy
BR9505366A (en) * 1995-12-06 1996-06-18 Protta Ind E Comercio De Produ Production process of bee venom-based ointment with analgesic and anti-inflammatory properties and product obtained

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0342055A2 (en) * 1988-05-13 1989-11-15 Unilever Plc Use of pyroglutamic acid alkyl esters for the manufacture of a medicament for the treatment of ichthyosis
WO1996010013A1 (en) * 1994-09-27 1996-04-04 Ono Pharmaceutical Co., Ltd. Five membered heterocyclic compounds

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Publication number Publication date
GB9717156D0 (en) 1997-10-22
GB9717157D0 (en) 1997-10-22
GB2313058A (en) 1997-11-19
GB2313059B (en) 1998-01-21
GB9717155D0 (en) 1997-10-22
GB2313546A (en) 1997-12-03
GB2313058B (en) 1998-01-21
GB2313546B (en) 1998-01-21

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PCNP Patent ceased through non-payment of renewal fee

Effective date: 20020329