HK1134053A - Treatment of gastrointestinal disorders with cgrp antagonists - Google Patents

Description

Treatment of gastrointestinal disorders using CGRP antagonists

The present invention relates to a method for preventing and treating visceral pain and gastrointestinal disorders such as functional bowel disorders and inflammatory bowel diseases by administering an effective amount of a compound which is a CGRP antagonist.

Background

Technical Field

Viscera includes the organs of the abdominal cavity. Visceral associated pain can be divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered gastrointestinal disorders include functional bowel disorders (functional boweldisors) and inflammatory bowel diseases. These gastrointestinal disorders include a variety of conditions that are currently only moderately controlled, including gastroesophageal reflux (gastroesophageal reflux), dyspepsia, irritable bowel syndrome and functional abdominal pain syndrome (functional abdominal pain syndrome), Crohn's disease, ileitis (ileitis), and ulcerative colitis, as well as visceral pain that occurs regularly.

Irritable Bowel Syndrome (IBS), also known as "colonic hypersensitivity", "spastic colon" or "mucous colitis", is characterized by lower abdominal discomfort or pain associated with bowel movement disorders. The nature of the symptoms can vary from patient to patient, from significant constipation or diarrhea to significant pain.

The most common chronic gastrointestinal disorders affect about 20% of the world population. The biopsychosocial disorder involves a disorder of the nervous system, a change in intestinal motility and an increase in visceral sensitivity.

All of these disorders are caused by a dysregulation of the bidirectional communication between the intestine and its enteric nervous system and the brain (brain-gut axis) regulated by a variety of psychosocial and environmental factors (e.g., infection, inflammation). A number of neurotransmitters in the brain and intestine, including 5-hydroxytryptamine (5-HT, serotonin) and its 5-HT, which regulate GI activity₃And 5-HT₄A receptor. Current approaches to IBS patients are based on positive diagnosis of symptomatology, elimination of underlying organ disease, and the establishment of therapeutic trials. Traditional symptomatic therapy includes antidiarrheals, laxatives and bulking agents (drugs)/fibers, low dose tricyclic antidepressants, antispasmodics for pain, and 'replacement' therapies (e.g., psychotherapy, hypnotherapy).

There is limited scientific evidence to support this therapy. Novel methods include visceral analgesics and serotonin agonists and antagonists. In patients with severe diarrhea, 5-HT is indicated₃Receptor antagonists (e.g., alosetron) and selective M₃A type anticholinergic; in constipation patients, 5-HT is indicated₄Agonists (e.g., tegaserod); and in pain patients, alpha is indicated₂-adrenergic drugs (e.g. clonidine), cholecystokinin antagonists, kappa-opioid agonists (e.g. fedotozine) and neurokinin antagonists; some of these drugs are still under investigation. It is understood that the brain-gut axis is important in the development of effective therapies for IBS (med. science unit.2004, 10(6), RA 125-131).

Visceral hypersensitivity has been proposed as one of the three underlying mechanisms of IBS and is thus supported by the fact that: patients with IBS have an increased perception of visceral events. This visceral hypersensitivity appears to be the result of a high probability of sensitization to the visceral afferent mechanisms of peptidergic C-fibers. Those afferent C-fibers contain Calcitonin Gene-Related Peptide (CGRP) and this Peptide has been shown to be a pro-pain response (pronociceptive).

Summary of The Invention

It has now been found that the symptoms of IBS can be effectively prevented and their distressing effects substantially reduced by substances with antagonistic CGRP effects (CGRP antagonists) or substances that inhibit or reduce the release of CGRP from sensory nerve terminals (CGRP release inhibitors).

The invention therefore relates to the use of CGRP antagonists (a) and/or release inhibitors for combating IBS, including prophylaxis and active treatment. The use according to the invention preferably comprises monotherapy (monotherapy) with a single agent (single substance), but also combination therapy (combined therapy) with a plurality of agents (B) from the indicated active substances.

The invention also relates to the use of CGRP antagonists and/or release inhibitors for the preparation of a pharmaceutical composition for the treatment of IBS and corresponding pharmaceutical compositions containing one or more CGRP antagonists and/or release inhibitors as active substance.

Any pharmaceutically acceptable active substance that antagonizes the known effects of CGRP or inhibits the release of CGRP from sensory nerve endings may be used for the purposes of the present invention.

Detailed Description

Examples of CGRP antagonists include amino acid derivatives as described in International patent application PCT/EP97/04862 and non-peptide actives as described in the following International patent applications: PCT/EP03/11762, PCT/EP03/11763, PCT/EP2004/000087, PCT/EP2005/003094, PCT/US03/16576, PCT/US2004/040721, PCT/US2003/038799, PCT/US2005/010330, PCT/GB99/03154, PCT/US2004/007226, PCT/US2004/007289, PCT/US2004/007686, PCT/US2004/007678, PCT/US2004/007715, PCT/US2004/011254, PCT/US2004/010851, PCT/US2004/011280, PCT/US2004/020206, PCT/US2004/021888, PCT/US2004/020209, PCT/US2005/002199, PCT/US/031713, PCT/US/031617, PCT/US/031712, PCT/US/032036, PCT/US/032 032041, PCT/US 2005/3982, PCT/032036, PCT/US2005/032288, PCT/US2005/035654 and US 2006/0094707.

Examples of CGRP release inhibitors include serotonin 5-HT_1DAgonists such as avitriptan, eletriptan, naratriptan, rizatriptan, sumatriptan or zolmitriptan, and 5-HT_1F-agonists or NPY-agonists.

Among the above CGRP antagonists, the following compound (a) (for example) is useful for treating IBS, for preparing corresponding pharmaceutical compositions and as an ingredient of corresponding pharmaceutical compositions.

Accordingly, a first object of the present invention is the use of a CGRP antagonist (a) selected from the group consisting of the following, enantiomers, diastereomers, mixtures and salts thereof, especially pharmaceutically acceptable salts with organic or inorganic acids or bases, for the preparation of a medicament for the treatment of IBS:

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The medicament is one of the following pharmaceutical preparations:

capsules for powder inhalation containing 1mg of active substance (a);

inhalable solutions for nebulisers containing 1mg of active substance (a);

propellant-operated metered aerosol formulations containing 1mg of active substance (A);

nasal spray containing 1mg of active substance (a);

tablets containing 20mg of active substance (a);

capsules containing 20mg of active substance (a);

an aqueous nasal solution containing 10mg of active substance (A);

an aqueous nasal solution containing 5mg of active substance (a);

nasal suspension containing 20mg of active substance (A).

The specifically mentioned compounds (A) of the invention are described in the international patent applications PCT/EP97/04862 and PCT/EP2005/003094 and can be prepared according to the methods described in said applications.

The compounds are administered orally and the effective dose is from 0.01mg/kg to 100 mg/kg.

Terms and definitions used

The subject of the invention also includes compounds of the invention (including salts thereof) in which one or more hydrogen atoms (for example 1, 2, 3, 4 or 5 hydrogen atoms) are replaced by deuterium.

The compounds of the invention may have acidic groups (mainly carboxyl groups) and/or basic groups such as amino groups. Thus, the compounds of the present invention may be present as internal salts, as salts with pharmaceutically acceptable inorganic acids such as hydrobromic, phosphoric, nitric, hydrochloric, sulfuric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic acid, or as salts with organic acids such as malic, succinic, acetic, fumaric, maleic, mandelic, lactic, tartaric, citric acid; or in the form of a salt with a pharmaceutically usable base, such as an alkali metal hydroxide or alkaline earth metal hydroxide, for example sodium hydroxide or potassium hydroxide, or a carbonate, ammonia, zinc hydroxide or ammonium hydroxide, or an organic amine, such as diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine.

As mentioned above, the compounds of the invention can be converted into their salts, in particular for pharmaceutical use into their physiologically and pharmacologically acceptable salts. In one aspect, these salts may be in the form of the physiologically and pharmacologically acceptable acid addition salts of the compounds of formula I with inorganic or organic acids. On the other hand, if they contain phenolic OH groups, the compounds of the invention can also be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with alkali metal or alkaline earth metal cations as counterions. These acid addition salts can be prepared, for example, using the following acids: hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic, lactic, citric, tartaric, or maleic acid. Mixtures of the above acids may also be used. The alkali metal salts and alkaline earth metal salts of the compounds of the formula I are preferably the hydroxides and hydrides of the alkali metals and alkaline earth metals thereof, of which the hydroxides and hydrides of the alkaline earth metals, in particular of sodium and potassium, and particularly preferably of sodium and potassium hydroxide are preferred.

If the compounds of the invention have only one chiral element, they can be present as racemates, but they can also be obtained as pure enantiomers, i.e., in the form of (R) or (S). Preferred compounds are those which exist in the form of the racemate or the (R) form.

However, when more than one chiral element is present in the compounds of the invention, the application also includes the individual diastereomer pairs of the enantiomers present therein or mixtures thereof, as well as the individual optically active enantiomers which constitute the racemates described above.

The invention relates to the compounds in question, optionally in the form of their individual optical isomers, mixtures of individual enantiomers or racemates, in the form of their tautomers as well as in the form of the free bases or of the corresponding acid addition salts with pharmacologically acceptable acids, such as acid addition salts with hydrohalic acids (e.g. hydrochloric or hydrobromic acid) or organic acids (e.g. oxalic, fumaric, diglycolic or methanesulfonic acid).

Combination of

As mentioned above, the CGRP antagonists (a) of the invention may be used as monotherapy, but may also be used in combination with other active compounds (B) to treat IBS.

For this purpose, the compound (B) may be selected from: 5-HT₁Agonists, 5-HT₃Antagonists, 5-HT₄Agonist, mixed 5-HT₃antagonist/5-HT₄Agonists, serotonin norepinephrine reuptake inhibitors, antispasmodics, anticholinergics, laxatives, tranquilizers (balast), antidiarrheals, tricyclic antidepressants and SSRIs, opioids, local anesthetics, α 2 agonists, cannabinoids (cannabinoids), P2X3/P2X2/3 antagonists, CCK-antagonists, VR-1/TRPV1 antagonists, neurokinin antagonists, β 3-adrenoceptor agonists, NSAlD, COX 2 inhibitors and probiotics (probiotics) which may be combined with one or more inert conventional carriers and/or diluents such as corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, Carboxymethyl cellulose or fatty substances such as stearin, or suitable mixtures thereof, together in conventional galenic preparations, such as plain or coated tablets, capsules, powders, lozenges,Suspensions, solutions, metered dose aerosols or suppositories.

5-HT₁The agonist may be selected from the group consisting of avletriptan, eletriptan, naratriptan, rizatriptan, sumatriptan or zolmitriptan, or a pharmaceutically acceptable salt thereof.

5-HT₃The antagonist may be selected from alosetron, cilansetron, granisetron, or a pharmaceutically acceptable salt thereof.

5-HT₄The agonist is selected from tegaserod, prucalopride, or a pharmaceutically acceptable salt thereof.

Hybrid 5-HT₃antagonist/5-HT₄The agonist may be selected from renzapride, cisapride, or a pharmaceutically acceptable salt thereof.

The serotonin norepinephrine reuptake inhibitor may be selected from venlafaxine, duloxetine, and milnacipran, or a pharmaceutically acceptable salt thereof.

The antispasmodic agent is selected from pinaverium bromide, mebeverine, alverine, or their pharmaceutically acceptable salts.

The anticholinergic can be selected from zafirarnine, darifenacin, or its pharmaceutically acceptable salts.

The laxative is selected from lactulose and polyethylene glycol.

The tranquilizer is selected from methylcellulose and psyllium seed (psyllium).

The antidiarrheal agent is selected from loperamide, cholestyramine, or its pharmaceutically acceptable salt.

Tricyclic antidepressants and SSRIs may be selected from amitriptyline, imipramine, or pharmaceutically acceptable salts thereof.

The opioid may be selected from the group consisting of fedotozine, trimebutine, or pharmaceutically acceptable salts thereof.

The local anaesthetic may be selected from trimebutine or a pharmaceutically acceptable salt thereof.

The alpha 2 agonist may be selected from clonidine or pharmaceutically acceptable salts thereof.

The cannabinoid is selected from Rimonabant (remombantant) or a pharmaceutically acceptable salt thereof.

The neurokinin antagonist may be selected from the group consisting of epinastine, napandolant, or a pharmaceutically acceptable salt thereof.

The beta 3-adrenoceptor agonist may be selected from the group consisting of solabegron (solabegron) or YM178, or a pharmaceutically acceptable salt thereof.

The NSAID may be selected from the following: arofenac, acemetacin, aspirin, azathioprine, celecoxib, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid, meloxicam, naproxen, phenylbutazone, piroxicam, sulfasalazine, zomepirac, or a pharmaceutically acceptable salt thereof.

The COX 2 inhibitor may be selected from meloxicam, rofecoxib, valdecoxib, parecoxib, etoricoxib, celecoxib, or pharmaceutically acceptable salts thereof.

The probiotic bacteria may be of the genus bifidobacterium.

Preparation

The compounds prepared according to the invention can be administered alone or optionally in combination with other active substances for the treatment of migraine by intravenous, subcutaneous, intramuscular, intraarticular, intrarectal or intranasal route, by inhalation, topical, transdermal or oral administration, while aerosol formulations are particularly suitable for inhalation. These combinations may be administered simultaneously or sequentially.

Suitable forms for administration include, for example, tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The proportion of the one or more pharmaceutically active compounds should be from 0.1% to 90% by weight, preferably from 0.5% to 50% by weight, of the total composition weight, i.e. in an amount sufficient to reach the dosage range mentioned below.

These formulations may be administered orally in the form of tablets, powders in capsules (e.g., hard gelatin capsules), or as solutions or suspensions. When administered by inhalation, the active substance combinations can be administered in the form of a powder, an aqueous or hydroalcoholic solution or with the aid of a propellant gas formulation.

Preferably, therefore, the pharmaceutical preparation is characterized in that it contains one or more compounds of the formula I according to the preferred embodiments described above.

Oral administration of a compound of formula I is particularly preferred, and administration once or twice a day is most preferred. Suitable tablets may be obtained, for example, by mixing the active substance with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose; disintegrating agents such as corn starch or alginic acid; binders such as starch or gelatin; lubricants such as magnesium stearate or talc; and/or agents for delaying release such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablet may also comprise multiple layers.

Accordingly, coated tablets may be prepared by coating cores produced analogously to the tablets with substances conventionally used for tablet coatings, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core may also be composed of multiple layers in order to achieve delayed release or to prevent incompatibilities. Similarly, the tablet coating may consist of multiple layers, so that it is possible to use the excipients mentioned above for tablets to achieve delayed release.

Syrups containing the active substances of the invention or combinations thereof may also contain sweetening agents such as saccharin, cyclamate, glycerol or sugar and flavour enhancers such as flavourants (e.g. vanillin or citrus extract). It may also contain suspension aids or thickeners such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Capsules containing one or more active substances or combinations of active substances may be prepared, for example, by mixing the active substances with inert carriers, such as lactose or sorbitol, and filling the capsules with gelatin.

Suitable suppositories may be prepared, for example, by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycols or derivatives thereof.

Excipients that may be used include, for example, water; pharmaceutically acceptable organic solvents, such as paraffins (petroleum fractions), vegetable oils (e.g. arachis oil or sesame oil), mono-or polyhydric alcohols (e.g. ethanol or glycerol); carriers such as natural mineral powders (e.g. kaolin, clay, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates); sugars (e.g., sucrose, lactose, and glucose); emulsifiers (e.g., lignin, spent sulfurous acid liquor, methylcellulose, starch, and polyvinylpyrrolidone); and lubricating agents (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

For oral use, the tablets may obviously contain, in addition to the carrier described, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, as well as various other substances such as starch (preferably potato starch), gelatin and the like. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc may also be used to make tablets. In the case of aqueous suspensions, the active substance may be combined with various flavour enhancers or colouring agents in addition to the excipients mentioned above.

Method of treatment

The CGRP antagonists (a) of the invention are active in a visceral pain model in rodents. In this model, hypersensitivity is induced by colonic stimulation (e.g., by butyrate, trinitrobenzene sulfonic acid, or acetic acid instillation). Colorectal balloon dilation was used to induce painful behavior such as abdominal contractions (see Bourdu et al, Gastroenterology 2005, 128, 1996-2008; Diop et al, j. pharmacol. exp. ther.2002, 302, 1013-1022; pouurde et al, am. j. physiol.1997, 273, G191-G196).

Since these compounds reverse colonic hypersensitivity in the above mentioned models, it is claimed that the CGRP antagonists (a) of the invention are particularly useful for the treatment of visceral pain/hypersensitivity in patients with IBS, but also for colic pain and dysmenorrhea.

Claims (18)

1. Use of a CGRP antagonist (a) selected from the group consisting of enantiomers, diastereomers, mixtures thereof, and physiologically acceptable salts thereof, in the manufacture of a medicament for the prevention or treatment of visceral pain:

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2. Use of a CGRP antagonist (a) selected from the group consisting of enantiomers, diastereomers, mixtures thereof, and physiologically acceptable salts thereof, in the manufacture of a medicament for preventing or treating a gastrointestinal disorder:

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3. Use according to claim 1 or 2, characterized in that the visceral pain is selected from functional bowel disorders and inflammatory bowel diseases.

4. Use according to claim 3, characterized in that the functional bowel disorder is selected from the group consisting of gastroesophageal reflux, dyspepsia, irritable bowel syndrome and functional abdominal pain syndrome.

5. Use according to claim 3, characterized in that said inflammatory bowel disease is selected from the group consisting of Crohn's disease, ileitis and ulcerative colitis.

6. Use according to claim 3, characterized in that the functional bowel disorder is irritable bowel syndrome.

7. Use according to claim 1 or 2, characterized in that it is carried out as a monotherapy using a single active substance.

8. Use according to claim 7, characterized in that the medicament contains only one active substance.

9. Use according to claim 7, characterized in that the medicament is a formulation for oral administration.

10. Pharmaceutical composition for the treatment or prevention of visceral pain and gastrointestinal disorders, comprising as active substance one or more CGRP antagonists (a) selected from the group according to claim 1, optionally in admixture with one or more inert carriers and/or diluents.

11. The pharmaceutical composition according to claim 10 for the treatment or prevention of a disease selected from the group consisting of: functional bowel disorders such as gastroesophageal reflux, dyspepsia, irritable bowel syndrome and functional abdominal pain syndrome; or inflammatory bowel diseases such as Crohn's disease, ileitis, and ulcerative colitis.

12. A pharmaceutical composition according to claim 11 for use in the treatment or prevention of irritable bowel syndrome.

13. A pharmaceutical composition according to any one of claims 10 to 12 in a form suitable for oral administration.

14. A method for preventing or treating visceral pain, said method comprising administering to a patient in need of treatment an effective amount of a CGRP antagonist (a) selected from the group consisting of enantiomers, diastereomers, mixtures thereof, and physiologically acceptable salts thereof:

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15. The method according to claim 14, wherein the condition is a functional bowel disorder or inflammatory bowel disease.

16. The method according to claim 15, wherein the functional bowel disorder is gastroesophageal reflux, dyspepsia, irritable bowel syndrome or functional abdominal pain syndrome.

17. The method according to claim 14 or 15, wherein the disorder is irritable bowel syndrome.

18. The method according to claim 15, wherein the inflammatory bowel disease is crohn's disease, ileitis, or ulcerative colitis.