EP1085874A1 - Utilisation d'un antagoniste du recepteur nk-1pour le traitement de dysfonctionnements sexuels - Google Patents

Utilisation d'un antagoniste du recepteur nk-1pour le traitement de dysfonctionnements sexuels

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Publication number
EP1085874A1
EP1085874A1 EP99955425A EP99955425A EP1085874A1 EP 1085874 A1 EP1085874 A1 EP 1085874A1 EP 99955425 A EP99955425 A EP 99955425A EP 99955425 A EP99955425 A EP 99955425A EP 1085874 A1 EP1085874 A1 EP 1085874A1
Authority
EP
European Patent Office
Prior art keywords
sexual
treatment
receptor antagonist
disorders
sexual dysfunctions
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.)
Withdrawn
Application number
EP99955425A
Other languages
German (de)
English (en)
Inventor
Nadia Melanie Rupniak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Organon Pharma UK Ltd
Original Assignee
Merck Sharp and Dohme Ltd
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 Merck Sharp and Dohme Ltd filed Critical Merck Sharp and Dohme Ltd
Publication of EP1085874A1 publication Critical patent/EP1085874A1/fr
Withdrawn legal-status Critical Current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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines

Definitions

  • This invention relates to the treatment or prevention of sexual dysfunctions by the administration of a NK- 1 receptor antagonist, in particular.
  • a NK- 1 receptor antagonist in particular.
  • Sexual dysfunction is characterised by a disturbance in the processes that are involved in the sexual response cycle or by pain associated with sexual intercourse.
  • the sexual response cycle comprises the four phases of desire, excitement, orgasm and resolution. Disorders of sexual response may occur at one or more of these phases.
  • sexual dysfunctions cause marked distress and interpersonal difficulty.
  • the sexual dysfunctions include sexual desire disorders, sexual arousal disorders, orgasmic disorders and sexual pain disorders. None of these disorders is adequately treated with existing therapies.
  • male erectile disorder a sexual arousal disorder
  • vasoactive drugs such as papaverine or prostaglandin El which are injected directly into the corpus cavernosum. This treatment is undesirable, both due to the undesirable side-effects associated with the therapeutic agents and due to the methodology employed.
  • oral therapeutic agents have been tested, these have generally proved unsatisfactory because of their poor efficacy, their safety, or undesirable side-effects.
  • Neurokinin 1 (NK-1; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins. and in particular substance P.
  • Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (see, for instance. International (PCT) patent specification Nos. WO 95/16679, WO 95/18124 and WO 95/23798).
  • the present invention provides the use of 2- ⁇ -)-(l-(S)-(3,5- bis(trifluoromethyl)phenyl)-2-hych ye hoxy)-3- ⁇
  • the exceptional pharmacology of the NK-1 receptor antagonist of use in the present invention enables the treatment of sexual dysfunctions, without the need for concomitant therapy, and in particular, without the need for concomitant use of a serotonin agonist or an SSRI.
  • the exceptional pharmacology of the NK- 1 receptor antagonist of use in the present invention results in a rapid onset of action.
  • the present invention accordingly provides the use of 2-(R)-(l-(S)- (3,5-bis(trifluoiOmethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)- 4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of sexual dysfunctions.
  • the present invention also provides a method for the treatment or prevention of sexual dysfunctions, which method comprises the oral administration to a patient in need of such treatment of an effective amount of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(1.2.4-triazol-3-yl)methylmox ⁇ jhoHne, or a pharmaceutically acceptable salt thereof.
  • an oral pharmaceutical composition for the treatment of sexual dysfunctions which comprises 2-(R)-(l-(S)-(3,5-bis(t__fluoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • sexual dysfunctions includes sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorders, sexual dysfunction due to a general medical condition, substance-induced sexual dysfunction and sexual dysfunction not otherwise specified.
  • sexual dysfunctions may be further defined by the nature of the onset of the disorder: either lifelong type or acquired type; by the context in which the disorder occurs: either generalized type or situational type; and by the etiological factors associated with the disorder: either due to psychological factors or due to combined factors.
  • sexual desire disorders include hypoactive sexual desire disorder and sexual aversion disorder.
  • sexual arousal disorders include female sexual arousal disorder and male erectile disorder.
  • Orgasmic disorders include female orgasmic disorder, male orgasmic disorder and premature ejaculation.
  • sexual pain disorders include dyspareunia and vaginismus.
  • Sexual dysfunctions due to a general medical condition may result from neurological conditions (e.g.
  • multiple sclerosis spinal cord lesions, neuropathy and temporal lobe lesions
  • endocrine conditions e.g. diabetes melitus, hypothyroidism, hypogonadal states and pituitary dysfunction
  • vascular conditions and genitourinary conditions e.g. testicular disease, Peyronie's disease, urethral infections, postprostatectomy complications, genital injury or infection, atrophic vaginitis, infections of the vagina and external genitalia, postsurgical comphcations such as episiotomy scars, shortened vagina, cystitis, endometriosis. uterine prolapse, pelvic infections and neoplasms).
  • Substance-induced sexual dysfunction can occur in association with intoxication with the following classes of substance: alcohol; amphetamine (and amphetamine-like substances); cocaine: opioids; sedatives, hypnotic and anxiolytics; and other unknown substances.
  • a decrease in sexual interest and orgasmic disorders may also be caused by prescribed medication including antihypertensives, histamine ⁇ Vreceptor antagonists, antidepressants. neuroleptics, anxiolytics. anabohc steroids, and antiepileptics. Painful orgasm has been reported with fluphenazine, thioridazine and amoxapine.
  • Priapism has been reported with the use of chlorpromazine, trazodone and clozapme, and following penile injections of papaverine or prostaglandin. Selective serotonin reuptake inhibitors may cause decreased sexual desire or arousal disorders.
  • the term "sexual dysfunctions ' ' includes any of the aforementioned sexual dysfunctions, including loss of libido, resulting from other medical conditions, most especially resulting from depression and/or anxiety.
  • treatment' ' refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions.
  • the NK- 1 receptor antagonist of use in the present invention is the compound 2-(R)-(l-(S)-(3,5-bis(trifiuoromethyl)phenyl)-2- hydroxyethoxv)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmo_pholine, or a pharmaceutically acceptable salt thereof.
  • Suitable pharmaceutically acceptable salts of the NK-1 receptor antagonist of use in the present invention include acid addition salts which may for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succmic acid, acetic acid citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid Salts of amme groups may also comprise the quaternary ammonium salts m which the ammo nitrogen atom carries an alkyl alkenyl, alkynyl or aralkyl group
  • the compositions containing the NK-1 receptor antagonist of use according to the present invention are m unit dosage forms such as tablets, pills capsules wafers and the like Additionally the NK- 1 receptor antagonist of use according to the
  • sohd compositions such as tablets
  • the principal active ingredient is mixed with a pharmaceutical carriei e g conventional tabletmg ingredients such as corn starch, lactose, sucrose, sorbitol, talc stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e g water, to form a sohd preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof
  • these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules
  • This sohd preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0 1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose. polyvinyl-pyrrolidone or gelatin.
  • compositions of the present invention may also be administered via the buccal cavity using conventional technology, for example, absorption wafers.
  • compositions in the form of tablets, pills, capsules or wafers for oral administration are particularly preferred.
  • a minimum dosage level for the NK- 1 receptor antagonist is about lmg per day, preferably about 5mg per day and especially about lOmg per day.
  • a maximum dosage level for the NK-1 receptor antagonist is about 1500mg per day, preferably about lOOOmg per day and especially about 500mg per day.
  • the compounds are administered once a day. It will be appreciated that the amount of the NK- 1 receptor antagonist required for use in the treatment or prevention of sexual dysfunctions will vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the patient's physician or pharmacist.
  • the activity of the NK- 1 receptor antagonist of use in the present invention may be measured using the following assays:
  • ASSAY 1 NK-1 Receptor binding
  • NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) cells expressing the human NK- 1 receptor using a modification of the assay conditions described by Cascieri et al, J. Pharmacol. Exp. Ther., 1992, 42, 458. Typically, the receptor is expressed at a level of 3xl0 5 receptors per cell. Cells are grown in monolayer culture, detached from the plate with enzyme-free dissociation solution (Speciality Media Inc.), and washed prior to use in the assay, ⁇ s j. ⁇ yr 8 - substance P (O.
  • lnM 2000Ci/mmol; New England Nuclear
  • test compounds dissolved in 5 ⁇ l dimethylsulphoxide, DMSO
  • 5xl0 4 CHO cells Ligand binding is performed in 0.25ml of 50mM Tris-HCl, pH7.5, containing 5mM MnCl 2 , 150mM NaCl, 0.02% bovine serum albumin (Sigma), 50 ⁇ g/ml chymostatin (Peninsula), O.lnM phenylmethylsulphonyl fluoride, 2 ⁇ g/ml pepstatin, 2 ⁇ g/ml leupeptin and 2.8 ⁇ g/ml furoyl saccharine.
  • CNS-penetrant NK-1 receptor antagonists for use in the present invention can be identified by their ability to inhibit foot tapping in gerbils induced by anxiogenic agents (such as pentagastrin) or central infusion of NK- 1 receptor agonists such as GR73632, or caused by aversive stimulation such as foot shock or single housing, based on the method of Rupniak & Williams, Eur. J. Pharmacol., 1994, 265, 179.
  • test compounds Male or female Mongolian gerbils (35-70g) are anaesthetised by inhalation of an isoflurane/oxygen mixture to permit exposure of the jugular vein in order to permit administration of test compounds or vehicle in an injection volume of 5ml/kg i.v.
  • test compounds may be administered orally or by subcutaneous or intraperitoneal routes. A skin incision is then made in the midline of the scalp to expose the skull.
  • An anxiogenic agent e.g. pentagastrin
  • a selective NK-1 receptor agonist e.g.
  • GR73632 (d Ala[L-Pro 9 ,Me-Leu 10 ]-substance P-(7- 11)) is infused directly into the cerebral ventricles (e.g. 3pmol in 5 ⁇ l i.c.v., depending on test substance) by vertical insertion of a cuffed 27 gauge needle to a depth of 4.5mm below bregma. The scalp incision is closed and the animal allowed to recover from anaesthesia in a clear perspex observation box (25cm x 20cm x 20cm). The duration and/or intensity of hind foot tapping is then recorded continuously for approximately 5 minutes. Alternatively, the ability of test compounds to inhibit foot tapping evoked by aversive stimulation, such as foot shock or single housing, may be studied using a similar method of quantification.
  • ferrets Individually housed male ferrets (1.0 -2.5 kg) are dosed orally by gavage with test compound. Ten minutes later they are fed with approximately lOOg of tinned cat food. At 60 minutes following oral dosing, cisplatin (lOmg/kg) is given i.v. via a jugular vein catheter inserted under a brief period of halothane anaesthesia. The catheter is then removed, the jugular vein ligated and the skin incision closed. The ferrets recover rapidly from the anaesthetic and are mobile within 10-20 minutes. The animals are observed continuously during recovery from the anaesthetic and for 4 hours following the cisplatin injection, after which time the animals are killed humanely. The numbers of retches and vomits occurring during the 4 hours after cisplatin administration are recorded by trained observers.
  • ASSAY 4 Separation-Induced Vocalisation Male and female guinea-pigs pups are housed in family groups with their mothers and littermates throughout the study. Experiments are commenced after weaning when the pups are 2 weeks old. Before entering an experiment, the pups are screened to ensure that a vigorous vocalisation response is reproducibly elicited following maternal separation. The pups are placed individually in an observation cage
  • each pup receives an oral dose or an s.c. or i.p. injection of test compound or vehicle and is then immediately returned to the home cage with its mother and siblings for 30 to 60 minutes (or for up to 4 hours following an oral dose, dependent upon the oral pharmacokinetics of the test compound) before social isolation for 15 minutes as described above.
  • the duration of vocalisation on drug treatment days is expressed as a percentage of the pre-treatment baseline value for each animal.
  • CNS-penetrant refers to NK- 1 receptor antagonists which are able to inhibit NK- 1 receptor antagonist-induced foot-tapping in the gerbil as hereinafter defined.
  • hind foot-tapping in the gerbil induced by infusion of the NK-1 receptor agonist, GR73632 (d Ala[L-Pro 9 ,Me-Leu 10 ] -substance P- (7-11)), under anaesthesia, directly into the central ventricles is inhibited when a CNS-penetrant NK-1 receptor antagonist is administered intravenously immediately prior to GR73632 challenge, wherein hind foot- tapping over a period of five minutes following recovery from the anaesthesia is inhibited with an IDso ⁇ 3mg/kg, and preferably with an
  • the NK-1 receptor antagonist is administered orally, 1 hour prior to GR73632 challenge, wherein the foot- tapping over a period of five minutes following recovery from anaesthesia is inhibited with an IDso ⁇ 30mg/kg, and preferably with an IDso ⁇ lOmg/kg.
  • CNS-penetrant NK-1 receptor antagonists of use in the present invention are also effective in the attenuation of separation-induced vocalisations by guinea-pig pups as hereinafter defined.
  • a vocalisation response in guinea-pig pups is induced by isolation from their mothers and littermates, which response is attenuated when a CNS-penetrant NK-1 receptor antagonist is administered subcutaneously 30 minutes prior to isolation, wherein vocalisations during the first 15 minutes of isolation are attenuated with an ID ⁇ o ⁇ 20mg/kg, preferably with an IDso ⁇ lOmg/kg, and especially with an ID 50 ⁇ 5mg/kg.
  • the NK-1 receptor antagonist is administered orally, 4 hours prior to isolation, wherein vocalisations during the first 15 minutes of isolation are attenuated with an ID5o ⁇ 20mg/kg, preferably with an IDso ⁇ lOmg/kg, and especially with an A suitable selection cascade for NKi antagonists of use according to the present invention is as follows:
  • step (v) Determine activity of compounds in assays sensitive to conventional antidepressant/anxiolytic drugs (inhibition of pharmacologically evoked foot tapping in gerbils and/or inhibition of distress vocalisations in guinea-pig pups (Assay 4)).
  • Yet further preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK- 1 receptor binding criteria of step (i) which, in addition, have ⁇ 5-fold shift in affinity when incubated in the presence of human serum albumin (HSA) to show non-specific protein binding.
  • HSA human serum albumin
  • the NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methy_morpholine, the preparation of which is described in International Patent Specification No. WO 95/18124 and US Patent No. 5,612,337. In the aforementioned assays, this compound has the following activity:
  • the active ingredient, cellulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
  • the resulting granulation is then compressed into tablets containing 50mg, lOOmg and 300mg of the NK-1 receptor antagonist per tablet.

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'utilisation d'un antagoniste du récepteur NK-1 pour la fabrication d'un médicament, adapté à l'administration orale, destiné au traitement ou à la prévention de dysfonctionnements sexuels. L'invention concerne aussi des méthodes de traitement qui utilisent un tel antagoniste du récepteur NK-1 et des compositions pharmaceutiques le contenant.
EP99955425A 1998-06-11 1999-06-08 Utilisation d'un antagoniste du recepteur nk-1pour le traitement de dysfonctionnements sexuels Withdrawn EP1085874A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9812664 1998-06-11
GBGB9812664.2A GB9812664D0 (en) 1998-06-11 1998-06-11 Therapeutic use
PCT/GB1999/001808 WO1999064008A1 (fr) 1998-06-11 1999-06-08 Utilisation d'un antagoniste du recepteur nk-1pour le traitement de dysfonctionnements sexuels

Publications (1)

Publication Number Publication Date
EP1085874A1 true EP1085874A1 (fr) 2001-03-28

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EP99955425A Withdrawn EP1085874A1 (fr) 1998-06-11 1999-06-08 Utilisation d'un antagoniste du recepteur nk-1pour le traitement de dysfonctionnements sexuels

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Country Link
EP (1) EP1085874A1 (fr)
AU (1) AU4278899A (fr)
CA (1) CA2334607A1 (fr)
GB (1) GB9812664D0 (fr)
WO (1) WO1999064008A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7323462B2 (en) 2002-12-10 2008-01-29 Pfizer Inc. Morpholine dopamine agonists

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5612337A (en) * 1993-12-29 1997-03-18 Merck Sharp & Dohme Limited Substituted morpholine derivatives and their use as therapeutic agents
GB9523244D0 (en) * 1995-11-14 1996-01-17 Merck Sharp & Dohme Therapeutic agents
CA2273351A1 (fr) * 1996-12-02 1998-06-11 Merck Sharp & Dohme Limited Utilisation d'antagonistes du recepteur nk-1 dans le traitement des troubles de la sexualite

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9964008A1 *

Also Published As

Publication number Publication date
WO1999064008A1 (fr) 1999-12-16
CA2334607A1 (fr) 1999-12-16
AU4278899A (en) 1999-12-30
GB9812664D0 (en) 1998-08-12

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