MXPA97002732A - Use of indol derivatives for the treatment of different enfermeda - Google Patents

Abstract

The invention provides the use of a compound of formula I wherein R 1 and R 2 independently represent H or C 1 -C 6 alkyl or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of dermatological disorders, peripheral neuropathies, arthritis gastrointestinal or urogenital diseases, headache associated with substances or abstinence, tension headache, pediatric migraine, posttraumatic dysautonia cephagia, orofacial pain, allergic or chronic obstructive respiratory diseases, glaucoma or eye inflammation, or prophylaxis of migra

Description

USE PE DERIVATIVES OF INDOL PORE THE TR TIFIEMENT OF DIFERFNTFR DISEASES CRIIPQ DE Lñ INVENCIÓN 5 This invention refers to new uses of certain derivatives of mdol in the treatment or prophylaxis of + health disorders.

BACKGROUND OF THE INVENTION International Patent Application UO 92/06973 discloses a series of mdol derivatives that are potent serotonin (5-HT) agonists. These compounds are useful for treating disorders caused by poor serotonergic neurotransmission that include hypertension, depression, anxiety, eating disorders, obesity, drug abuse, cluster headache, migraine, chronic paroxysmal pain and migraine, and Arab pain associated with vascular disorders. The compounds covered by UO 92/06973 include: () -5- (methylammosul foni L et? L) -3- (N-rneti lpi rrol? Dm-2- i lrnet? L) - lH-? ndol (Example 50, known as CP 122, 28R) and (R) -5-- (metilarni nosul foni l et i 1) -3- (pyrroli di n-2- i linef 1) - lH-i ntjol (Example ñfi, known as CP-122, b38) ", - '5 It is known that OP-122,288 and CP 122, R3B exhibit potency against neuroemea lmation in the dura mater (US l ee and MP Moskowitz, Brain Research. 626 (1993), 103-305) DESCRIPTION OF FL INVENTION It has been found that the compounds of the formula I, wherein R1 and Rs independently represent H or C-L-C-S alkyl, and their pharmaceutically acceptable salts, are useful in a considerable number of conditions. These include: (a) Dermatological disorders such as psoriasis; eczema; derma itis atopic ec-zema + osa; itching (also known as intractable eating) including eating associated with liver cirrhosis, cancer, and dialysis; Burns; scalds; sunburn; insect stings; urticaria; and abnormalities of the sweat gland; bullous pemphigoid; photo-dermatosis; skin blisters; adult acne; smallpox and dermatitis herpeti form; (b) Peripheral neuropathies that include postherpetica neuralgia, diabetic neuropathies such as periuric polymeuropathy and radiculopathy; causalgia and sympathetic reflex dystrophy; neuralgia after astectomy; neuralgia and pain * postqui r-úr-gi co; vulvar vestibulitis; ghost pain; Talarnic syndrome (central pain after an attack); poro-runandibular joint syndrome; rnetatarsalgia (Morton's neuralgia); and neurogenic nerve compression pain caused by - for example, a prolapsed spinal disc or carpal or tarsal canal syndromes; (c) Arthritis, including osteoa tp is and reurnatoid arpis; lupus erythematosus general; f ibromyalgia; spondial lt i s ankylosing; and tendimtis; Gastrointestinal and urogenital gas diseases including cystitis, gastroesophageal reflux, gastritis, continence of needs, inflammatory bowel disease, irritable bowel syndrome, compounds are also effective in regulating gastrointestinal tract morbidity; ) Headache associated with substances or their withdrawal (for example, narcotic withdrawal), tension headache, pediatric migraine, migraine prophylaxis, and cephalgia disa? Tonoma postra urna i ca; (f) Pain gold fací al which includes pain of teeth and pain of dental origin, pain of the ears, pain TN3 (pain of the temporo-mandibular joint), breast pain, kidney pain, non-arthritic cervical pain and no rhinus and ulcers in the mouth Meniere's disease, and facial neuralgia at ipi ca; (g) Allergic and chronic obstructive diseases of the respiratory * which include rhinitis, conjunctivitis; bronchial edema; bronchial asthma; neurological pulmonary edema (syndrome of respiratory disease in adults); anaphylaxis and angiodena; (h) Glaucoma (also known as mucocular pressure) and ocular inflammation.

Thus, one aspect of the invention relates to the use of a compound of formula T, as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in any of the aforementioned conditions. Another aspect of the invention relates to a pharmaceutical formulation comprising a compound of formula T, as defined above, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluyont or vehicle, characterized in that the formulation is adapted to administer the skin. As discussed below, conventional methods can be used to prepare the topical formulation. The formulation can be adapted for skin administration to the exclusion of other administration routes. Another aspect relates to a method of use comprising administering a therapeutically effective amount of a compound of formula I, as or defined above, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment at any of the conditions mentioned above. Compounds of formula T, as defined above, may exist as opticals. The invention includes all optical isomers and mixtures thereof. However, Formul I compounds having stereochemistry (R) co or shown in Figure lfl are preferred.

The alkyl groups that R and R5 * may represent may be linear, cyclic or branched. However, it is preferred that R'1 and? each represent methyl. the compounds of formula I include CP-122,288, CP-122, 638 and (R) -5- (ainmosul foniirnenyl) -3- (N-met i Ipyrrole din-2-yl and 11) -m-indol. The action of the compounds of formula I on the prevention or alleviation of the conditions mentioned above is unexpected. Some of these conditions can be treated using capsaicin C (E) -NC (-h? Drox? - 3 ~ rnetoxi feni l) - inet 113-8 - rnetil 6-nonenarn? Dal, which is antagonistic to inflammation. neurogenic decreasing neuropeptide levels of neurons. However, the mode of action of capsaicin is totally different from that of the compounds of formula I. When administered to a patient, the capsaicm selectively activates primary sensory afferents to cause the release of substances known as "SP" (substance P). and "CGRP" (peptide related to the gene of calcí tonina) which cause flaming. The continuous action of capsaicin gives < Or do the results of the reduction of neuropneptum do? of primary sensory afferents, so that these nerves lose their ability to promote tissue inflammation. In this way, the initial action of capsaicma is usually to cause intense itching and other effects associated with neurogenic inflammation. In contrast, the compounds of formula I above suppress inflammation immediately and activate an inhibitory receptor located at sensory nerve terminals. Given this difference in function, the effects of the compounds of the formula T can not be predicted from the known effects of capsaicma; In addition, they do not have the undesirable effects caused by the initial inflammation experienced when capsules are administered. The pharmaceutically acceptable salts of the compounds of formula T include non-toxic acid addition salts, that is, salts that contain pharmaceutically acceptable anions. Particular salts are mentioned in UO 92/06973, which also describes methods of preparing the aforementioned compounds and formulations containing the compounds for administration to patients. However, at least for oral administration, smoking is the preferred salt. The compounds of formula I and their salts defined above can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. In this manner, the active compounds can be formulated for topical, oral, buccal, intranasal, parenteral (for example intravenous, int amuscular or subcutaneous) or rectal administration, or in a form suitable for inhalation or insufflation. In the The aforementioned patent application, UO 92/06973, describes formulation methods. The daily dose of the compound administered to a patient for treatment of the aforementioned conditions will be determined by a physician for a given patient but is generally typically 0.1-200 g of active ingredient per unit oral, parenteral or oral dose that could be administered, for example 1 or 4 times a day for an adult weighing 70 lg. In an aerosol formulation, each metered dose or "puff" may contain from 20μg to lOOOug of the compound and the daily dose will be from lOOug to 10mg. Nevertheless. it has been found that the compounds CP-122,288 and CP-122,638 and (R) -5- (arninosulphon I eti 1) -3- (N-methylpyrrolidin-2-lrnet? i) -IH-mdol several smaller orders are active at doses of magnitude. The typical unit dose for topical, oral, buccal, parenteral, intravenous, intramuscular or subcutaneous administration, rectal inhalation or insufflation will be from 1 nanogram to 200 ng for these compounds with a correspondingly reduced two. for aerosol formulations. The following tests are considered to give an indication of the efficacy of a test compound in most of the conditions mentioned above: (i) The effect of the compounds of the invention in the suppression of inflammation can be demonstrated by the Escott method. and Brain fBr. 1. P armacol. (1993), JLO, 772-775) in which edema is measured in the hind leg of the rat after stimulation of the saphenous nerve. The test compound is administered intravenously at different amounts and the results are recorded as the extravasation ratio of plasma in the paw after stimulated and unstimulated paw. Compound DP 122,288 was found to have a significant effect administered in amounts as low as 2 x 20"* • • • mol / 1 g [Kajekar, Br. 3. Pharmacol. (1995), J _ £, J 21 ,. di) The effect of a compound of the invention in the suppression of vasodilatation can be demonstrated by the Kajekar method and other TBr. 3. Phar acol. (1995), 115. 8P1 in which vasodilatation is measured in the hind paw of the rat two times after stimulation of the saphenous nerve .. The test compound is administered mt r-aveniently at different doses and the results are recorded as co-administered. the change in the increase in blood flow in the skin. It was found that CP-122,288 has a signiicant effect at such low doses as 2 x 10 -3-3 mol / i >; g.

The invention is illustrated with the following examples AXIS? PLQ I FORMULATION OF TOPICAL AQUEOUS CREAM 1 kg of aqueous BP cream contains omuliferous ointment (300 g), phenoxyethylene (10 g) and purified water (690 g). I kg of ointment contains a wax emulsifier (300 g), white petrolatum (500 g) and mineral oil (200 g).

E3EÍ1PLQ 2 FORMULATION OF CREMA 01 FOSA T OPTOA I r > lkg of oily cream BP contains ointment of wool alcohols (500 g), phenoxyethanol (10 g), dry magnesium sulfate (5 g) and distilled water (485 g). 1 kg of wool alcohol ointment contains wool alcohols (60 g), hard paraffm (240 g), white petrolatum (100 g) and mineral oil (600 g).

Claims (3)

1. NOVELTY OF THE INVENTION CLAIMS The use of a compound of formula L, wherein R3- and Rs independently represent H or C-Cto alkyl, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of metabolic disorders.
2. 2. The use of a compound of formula I, in accordance with claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of peripheral neuropathies.
3. 3. The use of a compound of formula I, in accordance with claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of arthritis. compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of gastrointestinal or urogenital diseases 5. The use of a compound of formula I in accordance with 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, pediatric migraine, post-anesthesia dyschatronic cephalgia or migraine prophylaxis. 6. The use of a compound or formula T of 10 according to claim 1, or a pharmaceutically acceptable salt thereof, or the manufacture of a medicament for the treatment of oro-facial pain. 7. The use of a compound of formula I according to claim 1, or a salt Pharmaceutically acceptable thereof, in the manufacture of a medicament > for the treatment of obstructive chronic allergic diseases of the respiratory tract. 8. The use of a compound of formula I in accordance with claim 1, or a 20 pharmaceutically thereof, in the manufacture of a medicament: > for the treatment of glaucoma or ocular inflammation. 9"- The use according to any one of claims 1 to 8, characterized in that R" 1- and R ^ 'R each represents methyl in the compound used. 10. The use according to any of the preceding claims characterized in that the compound of formula T is in the form of its fuinarate salt. 11. Use according to claim 1, characterized in that the medicament is for the treatment of pruritus. 12. The use according to any of the preceding claims, characterized in that the compound of formula E has stereic acid (R) as shown in formula 1A, 13. A pharmaceutical formulation comprising a compound of formula I, according to claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or vehicle, characterized in that the formulation is adapted for administration. in the skin