AU4340799A - Use of indole derivatives for the treatment of various diseases - Google Patents

Description

S F Ref: 372732D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Nam an Adrs Name and Address of Applicant: Actual Inventor(s):

S

55 S. 5 Pflzer Research and Development Company, N.V./S.A.

La Touche House International Financial Services Centre Dublin 1 REPUBLIC OF IRELAND Kathryn Louise Monkhouse, Paul Gupta, Shirley Jones, Juan Lahuerta, Gillian Christine Land, Susan Frances Robson, Gillian Mary Ryder Samuels, Alan Brian Wilson and Martin James Wythes Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Use of Indole Derivatives for the Treatment of Various Diseases Address for Service: Invention Title: The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845 New method of treatment This invention relates to new uses of certain indole derivatives in the treatment or prophylaxis of medical disorders.

International Patent Application WO 92/06973 discloses a series of indole derivatives which are potent serotonin (5-HT) agonists. These compounds are useful for treating disorders arising from deficient serotonergic neurotransmission comprising hypertension. depression, anxiety, eating disorders, obesity. drug :C abuse, cluster headache, migraine, pain and chronic paroxysmal hemicrania and headache associated with vascular disorders The compounds covered by WO 92/06973 include (R)-5-(methylaminosulphonylmethyl)-3-(N-methylpyrrolidin-2 ylmethyl)-1H-indole (Example 5A. known as CP-122.288) and (methylaminosulphonylmethyl)-3-(pyrrolidin-2-ylmethyl)-1H-indole (Example 6A.

known as CP-122.638).

It is known that CP-122.288 and CP-122.638 exhibit potency against neurogenic inflammation in dura mater [W.S Lee and M.A. Moskowitz. Brain Research 626 (1993). 303-305].

2 2** It has now been found that compounds of formula I.

R-

N

RINIHSOLV N

H

wherein R and R: independently represent H or Ci-C, alkyl. and their pharmaceutically acceptable salts, are useful in a considerable number of conditions These include dermatological disorders, such as psoriasis. eczema. atopic eczematous dermatitis: pruritis (also known as intractable itch) including itch associated with liver cirrhosis, cancer and haemodialysis. burns: scalds sunburn insect bites: urticaria; and sweat gland abnormalities: bullous pemphigoid: photo-dermatoses: skin blisters: adult acne; chicken pox; and dermatitis herpetiformis; peripheral neurophathies including postherpetic neuralgia, diabetic neuropathies such as peripheral polyneuropathy and radiculopathy: causalgia and reflex sympathetic dystrophy; post-mastectomy neuralgia: post-surgical neuralgia and pain; vulvar vestibulitis; phantom limb pain: thalamic syndrome (central post-stroke pain); temporo mandibular joint syndrome: metatarsalgia (Morton's neuralgia): and neurogenic pain from nerve compression caused, for example, by a prolapsed intervertebral disc or carpal and tarsal tunnel syndromes: c1 arthritis, including osteoarthritis and rheumatoid arthritis: systemic lupus erythrematosus: fibromyalgia: ankylosing spondilitis: and tendinitis.

o ga~trointestinal and urogenital diseases. including cystitis qastroesophargeil reflux: gastritis: urge continence, inflammatory bov.wel disease, irritable bowel syndrome: the compounds are also effective in regulating gastrointestinal tract motility: headache associated with substances or their withdrawal (eg drug withdrawal): tension headache: paediatnc migraine, prophylaxis of migraine, and posttraumatic dysautonomic cephalgia: orofacial pain including toothache and pain of dental origin earache TMJ 2: pain (temporal mandibular joint pain); sinus pain. myofacial pain: non-arthritic and non-musculoskeletal cervical pain: mouth ulcers. Meniere s disease and atypical facial neuralgia: allergic and chronic obstructive airways diseases including rhinitis: conjunctivitis: bronchial oedema; bronchial asthma; neurological pulmonary oedema (adult respiratory disease syndrome): anaphylaxis: and angioedema glaucoma (also known as intra-ocular pressure) and ocular inflammation.

Thus. one aspect of the invention relates to the use of a compound of formula I.

as defined above, or a pharmaceutically acceptable salt thereof, in the manufac- 3 ture of a medicament for use in any one of the above-mentioned conditions.

Another aspect of the invention relates to a pharmaceutical formulation comprising a compound of formula 1. as defined above, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant. diluent or carrier, characterized in that the formulation is adapted for administration to the skin. As mentioned below, conventional methods may be used to prepare the topical formulation. The formulation may be adapted for administration to the skin to the exclusion of other routes of administration Yet another aspect relates to a method of use in any one of the above-mentioned conditions which comprises administenng a therapeutically effective amount of a compound of formula I, as defined above. or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment The compounds of formula 1. as defined above. may exist as optical isomers The 15 invention includes all optical isomers and mixtures thereof However compounds of formula I having (R)-stereochemistry as shown in formula IA.

R

R'NHSO

H

S. are preferred.

SAlkyl groups which R' and R' may represent can be linear cyciic or branched However, it is preferred that R' and R' each reoresent methyl Compounds of formula I include CP-122.288. CP-122.638 and 5 -(aminosulphonylmethyl)-3- (N-methylpyrrolidin-2-ylmethyl)- 1 H-indole 2E The action of the compounds of formula I in preventing or alleviating the conditions mentioned above is unexpected Some of these conditions may be treated using capsaicin [(E)-N-[(4-hydroxy-3-methoxyphenyl)-methyl]-8-methyl-6nonenamide] which is known to antagonise neurogenic inflammation by depleting 4 neuropeptide levels from neurones. However, the mode of action of capsaicin is totally different from that of the compounds of formula I When administered to a patient, capsaicin selectively activates primary sensory afferents to cause the release of substances known as "SP" (substance P) and "CGRP" (calcitonin gene related peptide) which cause inflammation. The continued action of capsaicin results in the depletion of neuropeptides from the primary sensory afferents. so that these nerves lose their capacity to promote tissue inflammation Thus. the initial action of capsaicir is generally to cause intense itching and other effects associated with neurogenic inflammation. In contrast, the compounds of formula

I

above suppress inflammation immediately by activating an inhibitory receptor located at the sensory nerve ending. Given this difference in function. the effects of the compounds of formula I cannot be predicted from the known effects of capsaicin; furthermore, they do not have the undesirable effects caused by the initial inflammation experienced when capsaicin in administered Pharmaceutically acceptable salts of the compounds of formula I Include non-toxic acid addition salts, that is salts containing pharmacologically acceptable anions SParticular salts are mentioned in WO 92/06973. which also describes methods of preparing the compounds mentioned above and formulations containing the 20 compounds for administration to patients. However. at least for oral administration, the fumarate salt is preferred.

The compounds of formula I and their salts defined above may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.

Thus the active compounds may be formulated for topical, oral. buccal. intranasal.

parenteral intravenous, intramuscular or subcutaneous) or rectal administration, or in a form suitable for inhalation or insufflation. Formulation methods are described in the above-mentioned Patent Application WO 92/06973 The daily dose of the compound administered to a patient for treatment of the above-mentioned conditions will be determined by a physician for any given patient but in general it will be typically 0.1 2 0 0mg of active ingredient per unit oral, parenteral or buccal dose which could be administered, for example, 1 to 4 times daily for an adult weighing 70kg). In an aerosol formulation each metered dose or "puff" may contain from 20pg to 1000pg of the compound and the overall daily dose will be from 100pg to 10mg. However, it has been found that compounds CP-122.288 and CP-122,638 and (R)-5-(aminosulphonylmethyl)-3-(Nmethylpyrrolidin-2-ylmethyl)-1H-indole are active at doses several orders of magnitude less. The typical unit dose for topical, oral, buccal, intranasal, parenteral intravenous, intramuscular or subcutaneous), rectal, inhalation or insufflation administration will then be 1 nanogram 200mg for these compounds with a correspondingly reduced dose for aerosol formulations.

The following tests are believed to give an indication of a test compound's efficacy in the majority of the conditions mentioned above: 15 The effect of compounds of the invention in suppressing inflammation may be demonstrated by the method of Escott and Brain (Br J Pharmacol. (1993).

110, 772-776) in which oedema in the rat hind paw is measured after saphenous nerve stimulation. The test compound is administered intravenously at different amounts and the results are reccrded as the ratio of plasma extravasation in the o. 2c stimulated/unstimulated hind paw. It is found that compound CP 122.288 has a significant effect at administered amounts as low as 2 x 10'" mol/kg [Kajekar. Br J. Pharmacol. (1995), 115, 1-2].

(ii) The effect of a compound of the invention in suppressing vasodilation may be demonstrated by the method of Kajekar et al [Br. J Pharmacol (1995), 115.

8Pj in which vasodilation in the rat hind paw is measured after saphenous nerve stimulation. The test compound is administered intravenously at different doses and the results are recorded as the change in the increase in skin blood flow. It is found that CP-122.288 has a significant effect at doses as low as 2x10 mol/kg The invention is illustrated by the following examples Example 1.

Topical aqueous cream formulation Ingredient Quantity (g) (R)-5-(methylaminosulphonylmethyI)-3- 0.001 g (N-methylpyrrolid in -2-ylm ethyl)- 1 Hindole fumnarate Aqueous Cream BP 999.999g 1kg of Aqueous Cream BP contains emulsifying ointment (300g). phenoxyethanol (l0g) and purified water (690g). 1kg of emulsifying ointment contains emulsifying wax (300g), white soft paraffin (500g) and liquid paraffin (200g).

Exmple 2 Topical oily cream formulation Ingredient IQuantity (g) (R)-5-(methylaminosulphonylmethyl)-3- 0.001 g (N-methylpyrrolidin-2-ylmethyl)-1

H-

indole fumarate Oily Cream 8P 999.999g 1Kg Of Oily Cream BP contains wooi alcohols ointment (500g), phenoxyethanol dried magnesium sulphate (5g) and purified water (485g). 1kg of wool alcohols ointment contains wool alcohols (60g), hard paraffin (240g). white soft paraffin (100g) and liquid paraffin (600g).

Claims (29)

1. A pharmaceutical composition comprising an effective amount of at least one compound of the formula R 2 N O 1 R O O H N H wherein R' and R 2 independently represent H or CI-Cs alkyl, or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, diluent or adjuvant therefor, characterised in that the composition is adapted for administration to the skin.

2. A composition as defined in claim 1 wherein R' and R 2 each represent o1 methyl.

3. A composition as defined in claim 1 or claim 2, wherein said compound is in the form of a fumarate salt.

4. A composition as defined in any one of claims 1 to 3, wherein the compound has the (R)-stereochemistry: O H H A pharmaceutical composition, substantially as hereinbefore described with reference to any one of the examples.

6. A method for the treatment or prophylaxis of dermatological disorders, peripheral neuropathies, arthritis, gastrointestinal or urogenital diseases, headache associated with substances or their withdrawal, tension headache, paediatric migraine, post-traumatic dysautonomic cephalgia, migraine, orofacial pain, allergic or chronic obstructive airways diseases, glaucoma, ocular inflammation or pruritis in a mammal requiring said treatment or prophylaxis, which method comprises administering to said mammal an effective amount of at least one compound of the formula IR \LIBA]02719 doctlt 8 R 2 N O 1 R O O H N H wherein R' and R 2 independently represent H or Ci-C 5 alkyl, or a pharmaceutically acceptable salt thereof, of a pharmaceutical composition containing said compound or of a pharmaceutical composition as defined in any one of claims 1 to S7. The method according to claim 6, wherein RI and R 2 each represent methyl.

8. The method as defined in claim 6 or claim 7, wherein said compound is in the form of a fumarate salt.

9. The method as defined in any one of claims 6 to 8, wherein the compound 10 has the (R)-stereochemistry: R2 R N 0 N 1 N O H N H H The method according to any one of claims 6 to 9, for the treatment or prophylaxis of dermatological disorders.

11. The method according to any one of claims 6 to 9, for the treatment or prophylaxis of peripheral neuropathies.

12. The method according to any one of claims 6 to 9, for the treatment or prophylaxis of arthritis.

13. The method according to any one of claims 6 to 9, for the treatment or prophylaxis of gastrointestinal or urogenital diseases.

14. The method according to any one of claims 6 to 9, for the treatment or prophylaxis of headache associated with substances or their withdrawal. The method according to any one of claims 6 to 9, for the treatment or prophylaxis of tension headaches. IR \LIBA]02719 doc it IC- rr l~r- 9

16. The method according to any one of claims 6 prophylaxis of paediatric migraine.

17. The method according to any one of claims 6 prophylaxis of post-traumatic dysautonomic cephalgia.

18. The method according to any one of claims 6 prophylaxis of migraine.

19. The method according to any one of claims 6 prophylaxis of orofacial pain. The method according to any one of claims 6 1 prophylaxis of allergic or chronic obstructive airways disease.

21. The method according to any one of claims 6 prophylaxis of glaucoma.

22. The method according to any one of claims 6 prophylaxis of ocular inflammation. 1 5

23. The method according to any one of claims 6 prophylaxis of pruritis.

24. Use of a compound of formula I, for the treatment or for the treatment or for the treatment or for the treatment or for the treatment or for the treatment or for the treatment or for the treatment or a a a. a N H wherein R' and R 2 independently represent H or Cl-C 5 alkyl, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of dermatological disorders. Use of a compound of Formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of peripheral neuropathies.

26. Use of a compound of Formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of arthritis.

27. Use of a compound of Formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of gastrointestinal or urogenital diseases. [R \LIBA]02719.doctlt 1

28. Use of a compound of Formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of headache associated with substances or their withdrawal; tension headache; paediatric migraine; post-traumatic dysautonomic cephalgia; or prophylaxis of migraine.

29. Use of a compound of Formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of orofacial pain. Use of a compound of Formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the I0 treatment of allergic or chronic obstructive airways diseases.

31. Use of a compound of Formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of glaucoma or ocular inflammation.

32. The use as claimed in any one of claims 24 to 31, wherein R' and R 2 each o ses i 15 represent methyl.

33. The use as claimed in any one of claims 24 to 31, wherein the compound of formula I is in the form of its fumarate salt.

34. The use as claimed in claim 24, wherein the medicament is for the treatment of pruritis. 99o S 20 35. The use as claimed in any one of claims 24 to 31, wherein the compound of formula I has (R)-stereochemistry as shown in formula IA: 2 R\ 2 N /IA R 1 NHS02" N H

36. A pharmaceutical formulation comprising a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, characterized in that the formulation is adapted for administration to the skin.

37. A method of treatment of: dermatological disorders; peripheral neuropathies; 3o arthritis; [R.\LIBA102719.doc.tit gastrointestinal or urogenital diseases; headache associated with substances or their withdrawal; tension headache; paediatric migraine; post-traumatic dysautonomic cephalgia; or prophylaxis of migraine; orofacial pain; allergic or chronic obstructive airways diseases; or glaucoma or ocular inflammation; which comprises administering a therapeutically effective amount of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, to a patient I0 in need of such treatment or prophylaxis. Dated 29 July, 1999 Pfizer Research and Development Company N.V./S.A. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON S 00 0 6 ft.f [R \LIBA]02710 doc tit