WO1994012166A1 - Agents therapeutiques pour le traitement de la cachexie - Google Patents

Agents therapeutiques pour le traitement de la cachexie Download PDF

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Publication number
WO1994012166A1
WO1994012166A1 PCT/GB1993/002423 GB9302423W WO9412166A1 WO 1994012166 A1 WO1994012166 A1 WO 1994012166A1 GB 9302423 W GB9302423 W GB 9302423W WO 9412166 A1 WO9412166 A1 WO 9412166A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
medicament
acceptable salt
Prior art date
Application number
PCT/GB1993/002423
Other languages
English (en)
Inventor
Kartha Streekumaran Nair
Joseph Alfred Truglia
Brian Roy Holloway
Donald Stribling
Michael Hardman
Original Assignee
Zeneca Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Zeneca Limited filed Critical Zeneca Limited
Priority to AU55320/94A priority Critical patent/AU5532094A/en
Publication of WO1994012166A1 publication Critical patent/WO1994012166A1/fr

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide

Definitions

  • the present invention relates to 4- [2- [ (2-hydroxy-3- phenoxypropyl)amino] ethoxy] -N- (2-methoxyethyl)phenoxyacetamide, depicted herei below as formula (I) wherein R is -NHCH CH OCH , and the acid metabolite thereof wherein R is -OH.
  • the present invention relates to these compounds and in particular to their use in the therapeutic treatment of animals including humans.
  • the compounds of the formula (I) have been shown to be selective ⁇ -adrenoceptor agonists in animals [Holloway et al., British Journal of Pharmacology , (1991) , 104, 97-104] . That is they stimulate thermogenesis.
  • the administration of the compound of the formula (I) wherein R is methoxyethylamino selectively increased oxygen consumption and brown adipose tissue activity in rats. Oxygen consumption was potently stimulated during tests on dogs and cats.
  • thermogenesis Maximal effects on thermogenesis were achieved at doses that had only minimal effects on the heart rate and on tremor, that is the compound was selective as a ⁇ -adrenoceptor agonist with little or no effects on ⁇ - and ⁇ -adrenoceptors.
  • the administration of the compounds was therefore predicted to be of use in the treatment of obesity and related conditions such as non-insulin dependent diabetes associated with obesity.
  • the compounds have also been predicted to be beneficial in lowering triglyceride and cholesterol levels and in stimulating 'atypical' ⁇ -receptors in the gastro-intestinal tract and therefore inhibiting gastrointestinal motility.
  • the compounds of the formula (I) have also been suggested to be of value m the modification of carcass composition, for example, by increased catabolism of fat in meat producing animals sucn as cattle, pigs, sheep, goats and/or rabbits.
  • the compounds increase lean cody mass although they decrease fat content and body weight leading to an overall loss of weight.
  • the compounds are therefore of use in combatting medical conditions wherein such control of whole body protein turnover is thought to be beneficial especially wherein metabolic rate increase is not desirable.
  • These compounds may be used in the treatment of cachexia.
  • Cachexia is the loss of weight and condition associated with many forms of severe illness. Progressive weight loss is a characteristic feature of cancer.
  • the compounds of the formula (I) will be of particular value n treating cancer cachexia.
  • the compounds of the formula (I) will also be of value in treating related conditions such as cachexia associated with trauma, burns, AIDS, anorexia nervosa and surgery and in treating negative nitrogen balance m intensive care patients and the elderly Furthermore, the compounds of the formula (I) have little or no effect on the ⁇ and ⁇ -adrenoceptors so that the treatment of cachexia patients, who are often very ill, has minimal undesirable side-effects .
  • the present invention provides a method of treating cachexia whch comprises administering, to an animal in need thereof, a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides the use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cachexia.
  • the present invention provides the use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for lowering protein turnover.
  • the present invention provides a method of lowering protein turnover which comprises administering, to an animal in need thereof, an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • R is 2-methoxyethylamino
  • the compounds of the formula (I) contain an asymmetric carbon atom and can exist as an optically active enantiomer (R or S according to the Cahn-Ingold-Prelog convention) or as an optically inactive racemate.
  • the compounds for use in the present invention contain at least some of the laevorotatory optically active form (-) which corresponds to (S) absolute configuration.
  • the compounds for use in the present invention are provided as the racemate but preferably are provided as the laevorotatory optically active form (- ⁇ .
  • the compounds of formula (I) are basic and may be isolated and used either m the form of a free base or of a pharmaceutically acceptable acid-addition salt thereof.
  • the compound of the formula (I) wherein R is hydroxy is ampnoteric and may be isolated and used in the zwitterionic form, or as a pharmaceutically acceptable acid-addition salt, or as a salt with a base affording a pharmaceutically acceptable cation.
  • Particular examples of pharmaceutically acceptable acid-addition salts include, for example, salts with inorganic acids such as hydrohalides (especially hydrochlorides or hydrobromides) , sulphates and phosphates, and salts with organic acids such as the free acid form of sulphonated polystyrene.
  • salts with bases affording a pharmaceutically acceptable cation include, for example, alkali metal and alkaline earth metal salts, such as sodium, potassium, calcium and magnesium salts, and ammonium salts and salts with suitable organic bases, such as triethanolamme.
  • a preferred compound for use in the methods of the present invention is :
  • the compound of the formula (I) and pharmaceutically acceptable salts thereof wherein R is hydroxy are known from, and/or can be prepared by, the methods of European Patent Application Publication No 210849.
  • the compounds of the formula (I) and pharmaceutically acceptable salts thereof wherein R s 2-methoxyethylam ⁇ no are known from, and/or can be prepared by, the methods of European Patent Application Publication No 254532.
  • the pnarmaceutical compositions of this invention may be administered in standard manner for example by oral or parenteral administration.
  • they may be formulated by means known to the art into the form of, for example, tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions, and sterile m * jectable aqueous or oily solutions or suspensions.
  • compositions for oral administration are preferred.
  • compositions may be obtained using standard excip ents and procedures well known in the art.
  • a unit dose form such as a tablet or capsule will usually contain 0.1-250mg of active ingredient, suitably 10-100 mg and typically 25 mg or 50 mg.
  • the compositions may be administered m conjunction with parenteral nutrition feeding fluids, for example Intralipid (Kabi Pharmacia) or appetite stimulants for example cyproheptadme.
  • parenteral nutrition feeding fluids for example Intralipid (Kabi Pharmacia) or appetite stimulants for example cyproheptadme.
  • the compounds of the formula (I) may also be used in combination with a low calorie diet in order to adjust protein metabolism to prevent loss of protem/lean-body mass whilst allowing weight loss through mobilisation of fat stores.
  • a compound of the formula (I) or a pharmaceutically acceptable salt When used to lower protein turnover in warm-blooded animals including humans, a compound of the formula (I) or a pharmaceutically acceptable salt will be administered so that a dose in the general range 0.002-20mg/kg, and preferably m the range 0.02-10mg/kg, is administered daily, given in a single dose or divided doses as necessary.
  • a dose in the general range 0.002-20mg/kg, and preferably m the range 0.02-10mg/kg is administered daily, given in a single dose or divided doses as necessary.
  • the dosage will necessarily be varied as appropriate, depending on the severity of the condition under treatment and on the age and sex of the patient and according to known medical principles
  • Volunteers receiving the compound experienced a mean decrease n weight of 0.57 kg. Volunteers treated with placebo experienced a mean decrease in body weight of 0.94 kg over the 14 day period.
  • Leucine oxidation was measured in accordance with the methodology of Nair et al. , Journal of Clinical Investigations 8_2, 198-205, 1988. The compound therefore had a statistically significant (p ⁇ .02) effect on leucme oxidation. This shows that the compound conserves or spares an essential amino-acid (leucine) and will have a beneficial effect on the maintenance of whole body protein.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne l'utilisation du 4-[2-[(2-hydroxy-3-phénoxypropyl)amino]éthoxy]-N-(2-méthoxyéthyl)phénoxy acétamide ou son métabolite d'acide correspondant, dans le traitement de la cachexie et en particulier de la cachexie liée au cancer.
PCT/GB1993/002423 1992-11-26 1993-11-25 Agents therapeutiques pour le traitement de la cachexie WO1994012166A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55320/94A AU5532094A (en) 1992-11-26 1993-11-25 Therapeutic agents for the treatment of cachexia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929224740A GB9224740D0 (en) 1992-11-26 1992-11-26 Therapeutic agents
GB9224740.2 1992-11-26

Publications (1)

Publication Number Publication Date
WO1994012166A1 true WO1994012166A1 (fr) 1994-06-09

Family

ID=10725688

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/002423 WO1994012166A1 (fr) 1992-11-26 1993-11-25 Agents therapeutiques pour le traitement de la cachexie

Country Status (5)

Country Link
AU (1) AU5532094A (fr)
GB (2) GB9224740D0 (fr)
IL (1) IL107767A0 (fr)
WO (1) WO1994012166A1 (fr)
ZA (1) ZA938803B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001035947A2 (fr) * 1999-11-15 2001-05-25 Eli Lilly And Company Traitement des syndromes cachectiques au moyen de propanolamines aryloxy

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0210849A1 (fr) * 1985-07-30 1987-02-04 Imperial Chemical Industries Plc 2-Hydroxy-3-phénoxypropylamines
EP0254532A1 (fr) * 1986-07-23 1988-01-27 Imperial Chemical Industries Plc Dérivés d'amides
EP0431763A2 (fr) * 1989-11-17 1991-06-12 Imperial Chemical Industries Plc Agents thérapeutiques pour diminuer les taux de triglycérides et/ou cholestérol et/ou pour augmenter ceux de HDL

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0210849A1 (fr) * 1985-07-30 1987-02-04 Imperial Chemical Industries Plc 2-Hydroxy-3-phénoxypropylamines
EP0254532A1 (fr) * 1986-07-23 1988-01-27 Imperial Chemical Industries Plc Dérivés d'amides
EP0431763A2 (fr) * 1989-11-17 1991-06-12 Imperial Chemical Industries Plc Agents thérapeutiques pour diminuer les taux de triglycérides et/ou cholestérol et/ou pour augmenter ceux de HDL

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001035947A2 (fr) * 1999-11-15 2001-05-25 Eli Lilly And Company Traitement des syndromes cachectiques au moyen de propanolamines aryloxy
WO2001035947A3 (fr) * 1999-11-15 2001-11-22 Lilly Co Eli Traitement des syndromes cachectiques au moyen de propanolamines aryloxy

Also Published As

Publication number Publication date
GB9324241D0 (en) 1994-01-12
ZA938803B (en) 1994-05-26
GB9224740D0 (en) 1993-01-13
IL107767A0 (en) 1994-05-30
AU5532094A (en) 1994-06-22

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