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WO2000028993A1 - Ligands de serotonine en tant que composes favorisant l'erection - Google Patents

Ligands de serotonine en tant que composes favorisant l'erection Download PDF

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Publication number
WO2000028993A1
WO2000028993A1 PCT/US1999/027484 US9927484W WO0028993A1 WO 2000028993 A1 WO2000028993 A1 WO 2000028993A1 US 9927484 W US9927484 W US 9927484W WO 0028993 A1 WO0028993 A1 WO 0028993A1
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WO
WIPO (PCT)
Prior art keywords
compound
compounds
receptor
combination
receptors
Prior art date
Application number
PCT/US1999/027484
Other languages
English (en)
Inventor
Eric S. Hayes
Original Assignee
Nortran Pharmaceuticals, Inc.
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 Nortran Pharmaceuticals, Inc. filed Critical Nortran Pharmaceuticals, Inc.
Priority to AU17389/00A priority Critical patent/AU1738900A/en
Publication of WO2000028993A1 publication Critical patent/WO2000028993A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines

Definitions

  • the present invention is generally directed to therapeutic agents, and in particular to agents that enhance sexual performance, such as pro-erectile compounds, and is also directed to composition containing these agents, and is also directed to therapeutic agents and composition that are characterized by one or more receptor activity profiles, and to methods of screening and identifying therapeutic agents according to their receptor activity profiles, and methods of treatment that employ such therapeutic agents and compositions.
  • the therapeutic agent may be employed to enhance sexual performance, as pro-libido agents and/or for the treatment and/or prevention of sexual dysfunction in males and/or females.
  • pharmacological agents used and/or reportedly useful as pro-libido agents and/or for the treatment of sexual dysfunction.
  • Some examples include: serotonin receptor agonists and antagonists (see, e.g., EP 385,658; WO 94/15,920; GB 2,248,449; and GB 2,276,165), dopamine receptor agonists (see, e.g., WO 93/23,035; WO 94/21,608; Pomerantz S. M., Pharmacol. Biochem. Behav. 39: 123-128, 1991; and Ferrari F. et al.
  • adrenergic receptor agonists see, e.g., WO 95/13,072; EP 611,248; US 5,229,387; and WO 92/1 1,851
  • inhibitors of phoshodiesterase see, e.g., DE 4,338,948; and WO 94/28,902
  • histamine receptor agonists see, e.g., US 4,013,659; US 4,126,670; US 4,767,778; WO 91/17,146; US 5,047,418; and EP 0,458,661
  • neuropeptide Y antagonists see, e.g., WO 95/00,161
  • angiotensin II receptor antagonists see, e.g., EP 577,025
  • cholinesterase inhibitors see, e.g., US 5,177,070; and US 4,633,318
  • nitric oxide donors see, e.g., WO 92/21,346; DE 4,305,881; DE 4,212,582; and WO 94/16,729); calcitonin gene related peptide (see, e.g., Steif, C. G. et al., Urology, 41:391-400, 1993); and androgens (see, e.g., JP 06,211,675; HU 62,473; and WO 94/16,709).
  • Dopamine receptor agonists may aggravate schizophrenia or induce it de novo in some patients.
  • Serotonin receptor agonists are capable of producing an effect that has been termed "serotonin syndrome" (Glennon, R.A. J. Med. Chem. 30:1-9,1987). This latter effect has been thoroughly investigated in animals (Peroutka, S. J. Science 212:821-829, 1981; Goddwin G. M. et al., Br. J. Pharmacol. 84:143-153, 1985; and Tricklebank, M. D., Eur. J. Pharmac.
  • Histamine receptor agonists may induce central nervous system dysfunction and adverse effects in the endocrine system.
  • Smooth muscle relaxants such as papaverine
  • -Adrenoreceptor blockers administered systemically have been reported to induce priapism characterized by a persistent erection that cannot be relieved by sexual intercourse or masturbation (Kaisary, A.V. et al., Br. J. Urol. 68:221, 1986).
  • the present invention provides for the use of a compound, or a combination of two or more compounds, for the manufacture of a medicament.
  • the compound or two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT 2 c and 5-HT 2A .
  • the compound or two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT 2A and 5-HT 3 .
  • the compound or two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT 2A and 5-HTIA-
  • the compound or two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT 2 c, 5- HT 2A , 5-HT 3 and 5-HT IA -
  • Such a medicament as described above may be used to achieve one or more of the following goals: treating and/or preventing sexual dysfunction in a patient; increasing the libido of a male or female patient; and enhancing the sexual performance of a male or female patient.
  • the present invention provides for the use of a compound or a combination of two or more compounds that can occupy the following serotonin (5- HT) receptors: 5-HT c and 5-HT 2A , for the manufacture of a medicament for the treatment or prevention of sexual dysfunction in a patient; the use of a compound or a combination of two or more compounds that can occupy the following serotonin (5- HT) receptors: 5-HT 2 c, 5-HT 2A and 5-HT 3 , for the manufacture of a medicament for the treatment or prevention of sexual dysfunction in a patient; the use of a compound or a combination of two or more compounds that can occupy the following serotonin (5-HT) receptors: 5-HT c, 5-HT 2A and 5-HT I A, for the manufacture of a medicament for the treatment or prevention of sexual dysfunction in a patient; the use of a compound or a combination of two or more compounds that can occupy the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT 2A , 5-HT 3 and
  • the present invention provides for the use of a compound or a combination of two or more compounds that can occupy the following serotonin (5- HT) receptors: 5-HT 2 c and 5-HT A , for the manufacture of a medicament for increasing the libido of a male or female patient; the use of a compound or a combination of two or more compounds that can occupy the following serotonin (5- HT) receptors: 5-HT 2 c, 5-HT A and 5-HT 3 , for the manufacture of a medicament for increasing the libido of a male or female patient; the use of a compound or a combination of two or more compounds that can occupy the following serotonin (5- HT) receptors: 5-HT c, 5-HT 2A and 5-HT ⁇ A , for the manufacture of a medicament for increasing the libido of a male or female patient; the use of a compound or a combination of two or more compounds, that can occupy the following serotonin (5- HT) receptors: 5-HT 2 c
  • the present invention provides for the use of a compound or a combination of two or more compounds, that can occupy the following serotonin (5- HT) receptors: 5-HT 2 c and 5-HT 2A , for the manufacture of a medicament for enhancing the sexual performance of a male or female patient; the use of a compound or a combination of two or more compounds that can occupy the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT 2A and 5-HT 3 , for the manufacture of a medicament for enhancing the sexual performance of a male or female patient; the use of a compound or a combination of two or more compounds that can occupy the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT 2A and 5-HT ⁇ , for the manufacture of a medicament for enhancing the sexual performance of a male or female patient; the use of a compound or a combination of two or more compounds that can occupy the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT 2A ,
  • the present invention further provides for the use of a compound or a combination of two or more compounds that can occupy the following serotonin (5- HT) receptors: 5-HT c and 5-HT A , for the manufacture of a medicament for the treatment or prevention of sexual dysfunction in a patient; or for the manufacture of a medicament for increasing the libido of a male or female patient, or for the manufacture of a medicament for enhancing the sexual performance of a male or female patient.
  • the compound or the combination of two or more compounds provides agonist activity at the 5-HT c receptor and antagonist activity at the 5-HT A receptor.
  • the present invention further provides for the use of a compound or a combination of two or more compounds that can occupy the following serotonin (5- HT) receptors: 5-HT 2 c, 5-HT 2A and 5-HT 3 , for the manufacture of a medicament for the treatment or prevention of sexual dysfunction in a patient; or for the manufacture of a medicament for increasing the libido of a male or female patient, or for the manufacture of a medicament for enhancing the sexual performance of a male or female patient.
  • the compound or the combination of two or more compounds provides agonist activity at the 5-HT 2 c receptor, antagonist activity at the 5-HT 2A receptor and neutral or agonist or antagonist activity at the 5-HT 3 receptor.
  • the present invention further provides for the use of a compound or a combination of two or more compounds that can occupy the following serotonin (5- HT) receptors: 5-HT c, 5-HT A and 5-HTI A , for the manufacture of a medicament for the treatment or prevention of sexual dysfunction in a patient; or for the manufacture of a medicament for increasing the libido of a male or female patient, or for the manufacture of a medicament for enhancing the sexual performance of a male or female patient.
  • the compound or the combination of two or more compounds provides agonist activity at the 5-HT c receptor, antagonist activity at the 5-HT 2A receptor and partial agonist activity at the 5-HT ⁇ receptor.
  • the present invention further provides for the use of a compound or a combination of two or more compounds that can occupy the following serotonin (5- HT) receptors: 5-HT 2 c, 5-HT 2A , 5-HT 3 and 5-HT JA , for the manufacture of a medicament for the treatment or prevention of sexual dysfunction in a patient; or for the manufacture of a medicament for increasing the libido of a male or female patient, or for the manufacture of a medicament for enhancing the sexual performance of a male or female patient.
  • the compound or the combination of two or more compounds provides agonist activity at the 5-HT c receptor, antagonist activity at the 5-HT 2 A receptor, neutral or agonist or antagonist activity at the 5-HT 3 receptor and partial agonist activity at the 5-HT IA receptor.
  • the compound or the combination of two or more compounds may be formulated for oral administration. In another embodiment, the compound or the combination of two or more compounds is formulated for topical administration. In another embodiment, the compound or the combination of two or more compounds is formulated for direct injection. In another embodiment, the compound or the combination of two or more compounds is formulated for one of intrameatal, intracavernous or intraurethral administration. In another embodiment, the compound or the combination of two or more compounds is formulated as a tablet with a disintegration time of less than one hour.
  • the compound or combination of two or more compounds does not interact with the alpha-adrenoceptors and furthermore optionally does not interact with the 5- HT IB receptor and/or 5-HT B receptor. In another optional embodiment of the above- described uses of the present invention, the compound or combination of two or more compounds does not interact with the 5-HTIB receptor and/or 5-HT 2B receptor.
  • the present invention provides pharmaceutical compositions.
  • the compositions comprise a pharmaceutically acceptable carrier or diluent and a compound or a combination of two or more compounds having the properties described above.
  • the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT 2 c and 5-HT 2A .
  • the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT 2A and 5-HT 3 .
  • the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT c, 5-HT 2A and 5-HT IA -
  • the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT 2A , 5- HT 3 and 5-HT JA -
  • the pharmaceutical composition may be in the form of a tablet for oral administration, where the tablet preferably has a disintegration time of less than one hour.
  • the present invention provides for a method for treating or preventing sexual dysfunction in a patient, comprising administering to the patient in need thereof a therapeutically effective dose of a compound, or a therapeutically effective dose of a combination of two or more compounds, or a therapeutically effective dose of a pharmaceutical composition comprising a compound, or a therapeutically effective does of a pharmaceutical composition comprising a combination of two or more compounds.
  • the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT c and 5-HT A -
  • the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT c, 5-HT 2A and 5-HT 3 .
  • the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT A and 5-HT IA - In another embodiment, the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT A , 5-HT 3 and 5-HT IA -
  • the therapeutically effective dose may achieve, for example, treatment and/or prevention of sexual dysfunction, where exemplary sexual dysfunction include male erectile dysfunction, impotence, or female sexual arousal disorder and/or female inhibited orgasm.
  • exemplary sexual dysfunction include male erectile dysfunction, impotence, or female sexual arousal disorder and/or female inhibited orgasm.
  • the therapeutically effective does may achieve, for example, an increase in the libido of a male or female patient.
  • the therapeutically effective does may achieve, for example, an enhancement in the sexual performance of a male or female patient.
  • the present invention also provides a method for increasing the libido of a male or female patient, comprising administering to the patient in need thereof a therapeutically effective dose of a compound, or a therapeutically effective dose of a combination of two or more compounds, or a therapeutically effective dose of a pharmaceutical composition comprising a compound, or a therapeutically effective dose of a pharmaceutical composition comprising a combination of two or more compounds.
  • the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT 2 c and 5-HT 2A -
  • the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT 2c , 5-HT 2A and 5-HT 3 .
  • the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT 2A and 5-HT IA - In another embodiment, the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT 2A , 5-HT 3 and 5-HT[ A -
  • the present invention also provides a method for enhancing the sexual performance of a male or female patient, comprising administering to the patient in need thereof a therapeutically effective dose of a compound, or a therapeutically effective dose of a combination of two or more compounds, or a therapeutically effective dose of a pharmaceutical composition comprising a compound, or a therapeutically effective dose of a pharmaceutical composition comprising a combination of two or more compounds.
  • the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5-HT 2 c and 5-HT 2A -
  • the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5- HT 2 c, 5-HT 2A and 5-HT 3 .
  • the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5- HT 2 c, 5-HT 2A and 5-HT 1A .
  • the compound or combination of two or more compounds can occupy the following serotonin (5-HT) receptors: 5- HT 2 c, 5-HT 2 A, 5-HT 3 and 5-HT IA -
  • the dose provides a pro- erectile response in the patient.
  • the present invention provides a method for treating or preventing sexual dysfunction in a patient, or increasing the libido of a male or female patient, or enhancing the sexual performance of a male or female patient.
  • the method comprises administering to the patient in need thereof a therapeutically effective dose of a compound, or a combination of two or more compounds that can occupy the following serotonin (5-HT) receptors: 5-HT 2 c and 5-HT 2A -
  • the compound or the combination of two or more compounds provides agonist activity at the 5-HT 2 c receptor and antagonist activity at the 5-HT receptor.
  • the present invention provides a method for treating or preventing sexual dysfunction in a patient, or increasing the libido of a male or female patient, or enhancing the sexual performance of a male or female patient.
  • the method comprises administering to the patient in need thereof a therapeutically effective dose of a compound, or a combination of two or more compounds that can occupy the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT 2A and 5-HT 3 .
  • the compound or combination of two or more compounds provides agonist activity at the 5-HT 2 c receptor, antagonist activity at the 5-HT 2A receptor and neutral or agonist or antagonist activity at the 5-HT 3 receptor.
  • the present invention provides a method for treating or preventing sexual dysfunction in a patient, or increasing the libido of a male or female patient, or enhancing the sexual performance of a male or female patient.
  • the method comprises administering to the patient in need thereof a therapeutically effective dose of a compound, or a combination of two or more compounds that can occupy the following serotonin (5-HT) receptors: 5-HT 2c , 5-HT A and 5-HT I A-
  • the compound or combination of two or more compounds provides agonist activity at the 5-HT 2 c receptor, antagonist activity at the 5-HT 2 A receptor and partial agonist activity at the 5-HT 1A receptor.
  • the present invention provides a method for treating or preventing sexual dysfunction in a patient, or increasing the libido of a male or female patient, or enhancing the sexual performance of a male or female patient.
  • the method comprises administering to the patient in need thereof a therapeutically effective dose of a compound, or a combination of two or more compounds that can occupy the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT 2A , 5-HT 3 and 5-HTIA-
  • the compound or combination of two or more compounds provides agonist activity at the 5-HT c receptor, antagonist activity at the 5-HT 2 A receptor, neutral or agonist or antagonist activity at the 5-HT 3 receptor and partial agonist activity at the 5-HT IA receptor.
  • the present invention provides a method of occupying the following serotonin (5-HT) receptors: 5-HT 2 and 5-HT 2A in a patient, comprising administering to the patient in need thereof a therapeutically effective dose of a compound or a combination of two or more compounds of the formula (I), while in a preferred embodiment, the compound or the combination of two or more compounds provides agonist activity at the 5-HT c receptor and antagonist activity at the 5-HT A receptor.
  • 5-HT serotonin
  • the present invention provides a method of occupying the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT 2A and 5-HT 3 in a patient, comprising administering to the patient in need thereof a therapeutically effective dose of a compound or a combination of two or more compounds of the formula (I), while in a preferred embodiment, the compound or the combination of two or more compounds provides agonist activity at the 5-HT 2 c receptor, antagonist activity at the 5-HT A receptor and neutral or agonist or antagonist activity at the 5-HT 3 receptor.
  • 5-HT serotonin
  • the present invention provides a method of occupying the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT 2A and 5-HT ⁇ A in a patient, comprising administering to the patient in need thereof a therapeutically effective dose of a compound or a combination of two or more compounds of the formula (I), while in a preferred embodiment, the compound or combination of two or more compounds provides agonist activity at the 5-HT 2 c receptor, antagonist activity at the 5-HT 2 A receptor and partial agonist activity at the 5-HT 1A receptor.
  • 5-HT serotonin
  • the present invention provides a method of occupying the following serotonin (5-HT) receptors: 5-HT 2 c, 5-HT A , 5-HT 3 and 5-HT I A in a patient, comprising administering to the patient in need thereof a therapeutically effective dose of a compound or a combination of two or more compounds of the formula (I), while in a preferred embodiment, the compound or combination of two or more compounds provides agonist activity at the 5-HT 2 c receptor, antagonist activity at the 5-HT A receptor, neutral or agonist or antagonist activity at the 5-HT 3 receptor and partial agonist activity at the 5-HT JA receptor.
  • 5-HT serotonin
  • Ar is selected from a C -C ⁇ 3 carbocyclic ring, a heteroaryl group, and ring systems selected from formulae (II), (III), (IV), (V), (VI), and (VII):
  • R 7 , R and R 9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen (H), hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C -C 7 alkanoyloxy, C ⁇ -C 6 alkyl, C ⁇ -C alkoxy, C -C 7 alkoxycarbonyl, C ⁇ -C 6 thioalkyl, aryl and N(R ⁇ 5 ,R ⁇ 6 ) where R ⁇ 5 and Ri 6 are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-C ⁇ alkyl;
  • R ⁇ 0 and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C ⁇ -C 6 alkyl, d- alkoxy, C -C 7 alkoxycarbonyl, Ci-C ⁇ thioalkyl, and N(R 1 s,R 16 ) where R 15 and R ⁇ 6 are independently selected from hydrogen, acetyl, methanesulfonyl, and C ⁇ -C 6 alkyl;
  • Rj is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, C 2 -C alkoxycarbonyl, C ⁇ -C 6 thioalkyl, and N(R 15 ,R ⁇ 6 ) where R ⁇ 5 and R ⁇ 6 are independently selected from hydrogen, acetyl, methanesulfonyl, and C ⁇ -C 6 alkyl; and Z is selected from CH , O, N and S, where Z may be directly bonded to "-CH C(O)-L-" as shown in formula (I) when Z is N, or Z may be directly bonded to Rj when Z is N, and R ⁇ 7 is selected from hydrogen, C ⁇ -C 6 alkyl, C 3 -Cgcycloalkyl,
  • L is selected from the group of a direct bond, O, NH, and
  • R 1 is selected from the group of a direct bond, a C ⁇ -C 6 alkylene group, and a 1 ,2-disubstituted C 5 -C 6 cycloalkyl;
  • R is selected from the group of H, a C ⁇ -C 6 alkyl and a C 7 -Cj 3 aralkyl.
  • the compound or combination of two or more compounds does not interact with the alpha-adrenoceptors, and furthermore, optionally, does not interact with the 5-HTI B receptor and/or 5-HT B receptor.
  • the compound or combination of two or more compounds does not interact with the 5-HT JB receptor and/or 5-HT 2B receptor.
  • the administration may be by oral administration, topical administration, direct injection, or one of intrameatal, intracavernous or intraurethral administration.
  • the present invention provides a method for screening test compounds for pro-erectile activity.
  • the method comprises:
  • the screening method additionally comprises; (c) contacting the test compound with a serotonin 5-HT 3 receptor, and measuring the binding of the test compound to the 5-HT 3 receptor.
  • the binding is measured by the %inhibition by the test compound on the binding of specific radioligand to the respective 5-HT subtype receptors (e.g., [3H]-Ketanserin for 5-HT 2A ; [3H]-Mesulergine for 5-HT 2C ; and [3H]-GR65630 for 5-HT 3 ).
  • the %inhibition is at least 30% and preferably 50% or more.
  • the compound is a piperazine derivative. The method may use a purified receptor.
  • Figure 1 is a graph showing the effects of Compound 1(4.0-64.0 mg/kg; i.p.) on erection ( ⁇ ; solid line) and latency to first erection (•; dashed line) in male rats compared to saline controls (C; empty symbols). Proportions above the data points indicate the number of test animals exhibiting erection at a given dose. Values represent mean ⁇ SEM for 10 test animals. An asterisk indicates a significant difference versus saline treated animals as determined by ANOVA (p ⁇ 0.05).
  • Figure 2 is a graph showing the effects of Compound 1(2.0-64.0 mg/kg; •, solid line), RSD1026 (2.0-32.0 mg/kg; ⁇ , dashed line) and RSD1052 (2.0- 32.0 mg/kg; ⁇ , stippled line) on erections in isolated male rats compared to saline controls (C; ⁇ ). Values represent mean ⁇ SEM for 10 test animals. An asterisk indicates a significant difference versus saline treated animals as determined by ANOVA (p ⁇ 0.05).
  • Figure 3 is a graph showing the effects of m-Chlorophenylpiperazine (m-CPP; 0.2-3.12 mg/kg; •, solid line), Trifluoromethylphenylpiperazine (TFMPP; 0.2-3.12 mg/kg; ⁇ , dashed line) and 1 -Naphthylpiperazine ( 1 -NP; 0.2-3.12 mg/kg; ⁇ , stippled line) on erections in isolated male rats compared to saline controls ( ⁇ ). Values represent mean ⁇ SEM for 10 test animals. An asterisk indicates a significant difference versus saline treated animals as determined by ANOVA (p ⁇ 0.05).
  • Figure 4 is a graph showing the effects of Cpd. 4 (0.1-10 mg/kg; •, solid line), Cpd. 5 (0.1-10 mg/kg; ⁇ , dashed line) and Cpd. 6 (0.1-10 mg/kg; ⁇ , stippled line) on erections in isolated male rats compared to saline controls ( ⁇ ). Values represent mean ⁇ SEM for 10 test animals. An asterisk indicates a significant difference versus saline treated animals as determined by ANOVA (p ⁇ 0.05).
  • Figure 7 is a graph showing the effects of NAN-190 (NAN; 0.2-2.0 mg/kg; i.p.; striped bars) on erections in male rats elicited by Compound 1 (992; 16 mg/kg; i.p.; cross hatched bars).
  • Control rats solid bars
  • saline Sal; 1.0 ml/kg; i.p.
  • An asterisk indicates significant difference compared to control rats whereas a + indicates a significant difference from animals receiving vehicle (saline) and Compound 1 (p ⁇ 0.05 by ANOVA with Dunnett's test for multiple comparisons).
  • Figure 8 is a graph showing the effects of saline (hatched columns), Compound 1 (solid columns), m-CPP (diagonal striped columns) and TFMPP (vertical striped columns) on erection (left side) and ejaculation (right side) in rats observed in pairs. Values represent mean ⁇ SEM for 15 test animals per group. An asterisk indicates significant difference compared to saline treated animals (p ⁇ 0.05; ANOVA with Dunnett's test for multiple comparisons).
  • Figure 9 is a graph showing the effects of saline (hatched columns), Compound 1 (solid columns), m-CPP (diagonal striped columns) and TFMPP (vertical striped columns) on rearing (left side) and movement (right side) in rats observed in pairs. Values represent mean ⁇ SEM for 15 test animals per group. An asterisk indicates significant difference compared to saline treated animals (p ⁇ 0.05; ANOVA with Dunnett's test for multiple comparisons).
  • Figure 10 is a graph showing the effects of saline (hatched columns),
  • Compound 1 (solid columns), m-CPP (diagonal striped columns) and TFMPP (vertical striped columns) on penile (left side) and non-penile (right side) grooming in rats observed in pairs. Values represent mean ⁇ SEM for 15 test animals per group. An asterisk indicates significant difference compared to saline treated animals (p ⁇ 0.05; ANOVA with Dunnett's test for multiple comparisons).
  • Figure 12 is a graph showing the lack of effect of Compound 1 on NA mediated contraction of rat vascular smooth muscle (aorta).
  • Figure 16 is a graph showing the effects of increasing doses of Compound 1 (10 "8 M ( ⁇ ), 10 “6 M ( ⁇ ), 10 “4 M (•)) and 1-naphthylpiperazine (3 x 10 "9
  • Figure 17 is a graph showing the effects of increasing doses of Compound 1 (92; 1.0-64.0 mg/kg; diagonal striped columns) on changes in core temperature in rats.
  • Saline (1.0 ml/kg) treated and 8-OHDPAT (0.65 mg/kg) treated control animals are represented by solid and cross hatched columns respectively.
  • Animals receiving Compound 1 at a dose of 64.0 mg/kg in the presence of saline are represented by a vertical striped column.
  • Pre-treatment and challenge are separated by a forward slash for saline (Sal), 8-OHDPAT (D) and Compound 1 (92(dose in parentheses)).
  • Ambient temperature ranged from 27.4-29.0 ° C.
  • Figure 18 is a graph showing the effects of increasing doses of Compound 1 (92; 2.0-32.0 mg/kg; diagonal striped columns) on changes in core temperature in rats.
  • Saline (1.0 ml/kg) treated and 8-OHDPAT (0.65 mg/kg) treated control animals are represented by solid and cross hatched columns respectively.
  • Animals receiving Compound 1 at a dose of 32.0 mg/kg prior to 8-OHDPAT (0.65 mg/kg) are represented by a vertical striped column.
  • Pre-treatment and challenge are separated by a forward slash for saline (Sal), 8-OHDPAT (D) and Compound 1 (92(dose in parentheses)).
  • Ambient temperature ranged from 27.0-29.0 ° C. Values are expressed as mean ⁇ SEM for 5 animals per test group.
  • An asterisk indicates a significant difference from saline treated controls (p ⁇ 0.05 ANOVA and Dunnett's test for multiple comparisons).
  • Figure 19 is a graph showing the inhibitory effects of Compound 1 (992; (2.0-32.0 mg/kg)); diagonal striped column) and ketanserin (Ket (1.0 mg/kg); horizontal striped column) on DOI (DOI (2.5 mg/kg); cross-hatched column) induced head-twitch responses. Head-twitch responses in animals receiving only saline are indicated by a solid column (C). Values represent the mean ⁇ SEM for the number of head-twitches scored for 10 minutes in 5 animals. An asterisk indicates a significant difference from saline controls whereas a + indicates a significant difference from DOI treated animals receiving saline (p ⁇ 0.05; ANOVA with Dunnett's test for multiple comparisons).
  • Figure 20 is a graph showing the effects of increasing doses of Compound 1 (•), quipazine ( ⁇ ), m-CPP ( ⁇ ), TFMPP( ⁇ ) and saline (V)on bradycardia induced by i.v administration of serotonin. Data are expressed as the reduction in heart rate in beats per minute after 5-HT administration. C indicates pre- drug responses to test doses of 5-HT. Values represent the mean ⁇ SEM for 6 experiments. An asterisk indicates a significant reduction the bradycardic response to 5-HT compared to pre-drug (p ⁇ 0.05; ANOVA).
  • a bond to a substituent and/or a bond that links a molecular fragment to the remainder of a compound may be shown as intersecting one or more bonds in a ring structure. This indicates that the bond may be attached to any one of the atoms that constitutes the ring structure, so long as a hydrogen atom could otherwise be present at that atom. Where no particular substituent(s) is identified for a particular position in a structure, then hydrogen(s) is present at that position.
  • the R groups may be present at different atoms of the ring, or on the same atom of the ring, so long as that atom could otherwise be substituted with a hydrogen atom.
  • the invention is intended to encompass compounds wherein -CH 2 C(O)-L- is joined through CH to the Ar group (V) at any atom that forms the group (V) so long as that atom of group (V) could otherwise be substituted with a hydrogen atom.
  • the R ⁇ 2 group would occupy one and only one of the remaining six positions, and hydrogen atoms would be present in each of the five remaining positions.
  • the compounds of the present invention may contain two or more asymmetric carbon atoms and thus exist as enantiomers and diastereomers.
  • the present invention includes all enantiomeric and diastereomeric forms of the compounds of the invention. Pure stereoisomers, mixtures of enantiomers and/or diastereomers, and mixtures of different compounds of the invention are included within the present invention. Thus, compounds of the present invention may occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. A racemate or racemic mixture does not imply only a 50:50 mixture of stereoisomers.
  • the compounds of formula (I) or formula (XX) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
  • independently at each occurrence is intended to mean (i) when any variable occurs more than one time in a compound of the invention, the definition of that variable at each occurrence is independent of its definition at every other occurrence; and (ii) the identity of any one of two different variables (e.g., Ri within the set Ri and R 2 ) is selected without regard the identity of the other member of the set.
  • substituents and/or variables are permissible only if such combinations result in stable compounds.
  • Acid addition salts refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, ⁇ -toluenesulfonic acid, salicylic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid
  • Alkanoyloxy refers to an ester substituent wherein the non-carbonyl oxygen is the point of attachment to the molecule.
  • Alkoxy refers to an O-atom substituted by an alkyl group, for example, methoxy [-OCH , a Ci alkoxy].
  • Alkoxyalkyl refers to an alkylene group substituted with an alkoxy group.
  • methoxyethyl [CH 3 OCH 2 CH 2 -] and ethoxymethyl (CH 3 CH 2 OCH 2 -] are both C 3 alkoxyalkyl groups.
  • Alkyl refers to a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms and having one point of attachment. Examples include w-propyl (a C 3 alkyl), z ' s ⁇ -propyl (also a C 3 alkyl), and t-butyl (a C 4 alkyl).
  • Alkylene refers to a divalent radical which is a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, and having two points of attachment.
  • An example is propylene [-CH CH 2 CH 2 -, a C 3 alkylene].
  • Alkylcarboxy refers to a branched or unbranched hydrocarbon fragment terminated by a carboxylic acid group [-COOH]. Examples include carboxymethyl [HOOC-CH 2 -, a C 2 alkylcarboxy] and carboxyethyl [HOOC-CH 2 CH 2 -, a C 3 alkylcarboxy].
  • Aryl refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl (also known as heteroaryl groups) and biaryl groups. Carbocyclic aryl groups are generally preferred in the compounds of the present invention, where phenyl and naphthyl groups are preferred carbocyclic aryl groups.
  • Alkyl refers to an alkylene group wherein one of the points of attachment is to an aryl group.
  • An example of an aralkyl group is the benzyl group [C 6 H 5 CH 2 -, a C 7 aralkyl group].
  • Cycloalkyl refers to a ring, which may be saturated or unsaturated and monocyclic, bicyclic, or tricyclic formed entirely from carbon atoms.
  • An example of a cycloalkyl group is the cyclopentenyl group (C H 7 -), which is a five carbon (C 5 ) unsaturated cycloalkyl group.
  • Carbocyclic refers to a ring which may be either an aryl ring or a cycloalkyl ring, both as defined above.
  • Carbocyclic aryl refers to aromatic groups wherein the atoms which form the aromatic ring are carbon atoms.
  • Carbocyclic aryl groups include monocyclic carbocyclic aryl groups such as phenyl, and bicyclic carbocyclic aryl groups such as naphthyl, all of which may be optionally substituted.
  • Heteroatom refers to a non-carbon atom, where boron, nitrogen, oxygen, sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygen and sulfur being particularly preferred heteroatoms in the compounds of the present invention.
  • Heteroaryl refers to aryl groups having from 1 to 9 carbon atoms and the remainder of the atoms are heteroatoms, and includes those heterocyclic systems described in "Handbook of Chemistry and Physics," 49th edition, 1968, R.C. Weast, editor; The Chemical Rubber Co., Cleveland, OH. See particularly Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitable heteroaryls include furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, and the like.
  • Hydroxyalkyl refers to a branched or unbranched hydrocarbon fragment substituted with an hydroxy (-OH) group. Examples include hydroxymethyl (-CH 2 OH, a Cihydroxyalkyl) and 1-hydroxyethyl (-CHOHCH 3 , a C 2 hydroxyalkyl).
  • Thioalkyl refers to a sulfur atom substituted by an alkyl group, for example thiomethyl (CH 3 S-, a Cjthioalkyl).
  • “Patient” refers to a warm-blooded animal such as a mammal which can and will benefit from the above treatment (curative or prophylactic). It is understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of male and female patients within the scope of the meaning of the term.
  • “Pharmaceutically acceptable carriers” for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remingtons Pharmaceutical Sciences. Mack Publishing Co. (A.R. Gennaro edit. 1985). For example, sterile saline and phosphate-buffered saline at physiological pH may be used. Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. For example, sodium benzoate, sorbic acid and esters of >-hydroxybenzoic acid may be added as preservatives. Id at 1449. In addition, antioxidants and suspending agents may be used. Id.
  • “Pharmaceutically acceptable salt” refers to salts of the compounds of the present invention derived from the combination of such compounds and an organic or inorganic acid (acid addition salts) or an organic or inorganic base (base addition salts).
  • the compounds of the present invention may be used in either the free base or salt forms, with both forms being considered as being within the scope of the present invention.
  • the "therapeutically effective amount” or the “therapeutically effective dose” of a compound of the present invention will depend on the route of administration, the type of warm-blooded animal being treated, and the physical characteristics of the specific warm-blooded animal under consideration. These factors and their relationship to determining this amount are well known to skilled practitioners in the medical arts. This amount and the method of administration can be tailored to achieve optimal efficacy but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • compositions described herein as "containing a compound of formula (I)” etc. encompass compositions that contain more than one compound of formula (I), etc.
  • compositions described herein as "containing a pro-erectile compound” or the like encompass compositions that contain more than one such compound.
  • the compounds of the present invention can occupy the following seretonin (5-HT) receptors: 5-HT C and 5-HT 2A .
  • the compounds of the present invention can occupy the following seretonin (5-HT) receptors: 5-HT 2 c, 5-HT 2A , and 5-HT 3 .
  • the compounds of the present invention can occupy the following seretonin (5-HT) receptors: 5-HT 2c , 5-HT 2A , 5-HT 3 and 5-HT 1A .
  • the compounds of the present invention can provide agonist activity at the 5-HT 2 receptor and antagonist activity at the 5-HT 2A receptor. In another aspect, the compounds of the present invention can provide agonist activity at the 5-HT c receptor, antagonist activity at the 5-HT 2A receptor and neutral or agonist or antagonist activity at the 5-HT 3 receptor.
  • the compounds of the present invention can provide agonist activity at the 5-HT 2 c receptor, antagonist activity at the 5-HT 2A receptor and partial agonist activity at the 5-HT IA receptor. In another aspect, the compounds of the present invention can provide agonist activity at the 5-HT 2 c receptor, antagonist activity at the 5-HT 2A receptor, neutral or agonist or antagonist activity at the 5-HT 3 receptor and partial agonist activity at the 5-HT IA receptor.
  • the compounds of the present invention do not interact with the alpha-adrenoceptors. In another aspect, the compounds of the present invention do not interact with the 5-HT IB receptor and/or 5-HT 2B receptor.
  • Ar is selected from a C 3 -C ⁇ carbocyclic ring, a heteroaryl group, and ring systems selected from formulae (II), (III), (IV), (V), (VI), and (VII):
  • R 7 , R 8 and R 9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen (H), hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C -C alkanoyloxy, C C 6 alkyl, C ⁇ -C 6 alkoxy, C 2 -C alkoxycarbonyl, C)-C thioalkyl, aryl and N(Ri 5 ,R ⁇ 6 ) where Rj 5 and Rj 6 are independently selected from hydrogen, acetyl, methanesulfonyl, and Ci-C ⁇ alkyl;
  • Rio and Rn are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 -C 7 alkanoyloxy, C]-C 6 alkyl, C ⁇ -C alkoxy, C 2 -C 7 alkoxycarbonyl, C ⁇ -C 6 thioalkyl, and N(Ri 5 ,R ⁇ 6 ) where R !5 and R )6 are independently selected from hydrogen, acetyl, methanesulfonyl, and C ⁇ -C 6 alkyl;
  • Rn is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C -C 7 alkanoyloxy, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, C -C alkoxycarbonyl, C ⁇ -C thioalkyl, and N(R ⁇ ,R ⁇ ) where R 15 and R ⁇ 6 are independently selected from hydrogen, acetyl, methanesulfonyl, and C ⁇ -C alkyl; and Z is selected from CH 2 , O, N and S, where Z may be directly bonded to "-CH 2 C(O)-L-" as shown in formula (I) when Z is N, or Z may be directly bonded to Rj 7 when Z is N, and R ⁇ is selected from hydrogen, C ⁇ -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl
  • L is selected from the group of a direct bond, O, NH, and N(C 1 -C 6 alkyl);
  • R 1 is selected from the group of a direct bond, a C ⁇ -C 6 alkylene group, and a 1 ,2-disubstituted Cs-C 6 cycloalkyl;
  • R is selected from the group of H, a C ⁇ -C 6 alkyl and a C 7 -C ⁇ 3 aralkyl.
  • l-Methyl-4-(2-naphthaleneacetyl)piperazine Compound 1
  • 1 -methyl - 4-(l-naphthaleneacetyl)piperazine Compound 2)
  • 2-(naphthylacetyl)piperazine Compound 7
  • l-(naphthylacetyl)piperazine Compound 8
  • Certain compounds of the invention may be prepared by a method wherein a substituted acetic acid compound or activated version thereof, having the formula
  • N-H functions e.g., in the form of a t-Boc (N-tert-butoxy-carbonyl) group
  • t-Boc N-tert-butoxy-carbonyl
  • Examples 3 and 4 illustrate the use of the t-Boc protective group in two different conjugation reactions. Conditions for removal of the t-Boc function are described also.
  • -OH may be prepared from the corresponding acid (where X is -OH).
  • acid starting materials such as 1 -naphthalene acetic acid, 2-naphthalene acetic acid, phenylacetic acid, bromophenylacetic acid (including the 2-, 3- and 4- positional isomers), methylphenylacetic acid (also known as tolylacetic acid) and many other compounds of the formula Ar-CH 2 -COOH are commercially available. See, e.g., Aldrich Chemical Co., Milwaukee, WI.
  • a substituted acetic acid may be reacted with, e.g., thionyl chloride, to prepare an activated substituted acetic acid compound.
  • Other synthetic protocols for preparing an activated acid may be found in, e.g., Szmuszkovicz, J.; Von Voigtlander, P.F. (1982) J. Med. Chem. 25: 1125-1126; U.S. Patent 5,506,257 to MacLeod B.A. et al., U.S. Patent 5,637,583 to MacLeod B.A. et al. and Clark, C.R. et al. (1988) J. Med. Chem. 31 : 831-836.
  • the activated substituted acetic acid compound is then reacted with an amine or alcohol compound (depending on the identity of L) of the formula
  • R 1 is a 1 ,2-disubstituted C 5 -C 6 cycloalkyl
  • the preparation of 1 ,2-diaminocyclohexyl intermediates is described in, e.g., Szmuszkovicz, J.; Von Voigtlander, P.F. (1982) J. Med. Chem. 25: 1125-1126; and U.S. Patent 5,506,257 to MacLeod B. A. et al.
  • the preparation of 1 -hydroxy-2-aminocyclohexyl intermediate is described in U.S. Patent 5,637,583, also to MacLeod B.A. et al.
  • the preparation of reactive carboxylic acid derivatives is described in the above references as well as in Clark, C. R. et al. (1988) J. Med. Chem. 31 : 831 -836.
  • the carboxylic acids may be coupled to the amine in the presence of a coupling reagent such as dicyclohexyl carbodiimide (DCC) or the like.
  • DCC dicyclohexyl carbodiimide
  • the reaction is generally carried out in a suitable solvent such as tetrahydrofuran or dioxane at ambient temperature, but depending upon the reactivity of the specific starting materials employed, the reaction time, solvent employed and reaction temperature may be varied without undue experimentation by one of ordinary skill in the art, to achieve the desired coupling reaction.
  • a reaction temperature of between about -25°C and the boiling point of the solvent are typically employed.
  • the reaction between the activated carboxylic acid (e.g., acid chloride) and the amine is generally carried out at ambient temperature in a suitable solvent such as chloroform or dichloromethane in the presence of an acid acceptor (i.e., base) such as a tertiary amine or an alkaline metal carbonate or bicarbonate.
  • an acid acceptor i.e., base
  • the mixture of amine and acid halide is allowed to react until the reaction is essentially complete.
  • 5-HT ⁇ -4 Molecular biological and biochemical techniques have confirmed the existence of at least 7 distinct 5-HT receptor types containing an unprecedented total of 15 subtypes (Saudou & Hen, 1995, Adv. Pharmacol. 327; Peroutka, 1994, Neurochem. Int. 533).
  • 5-HT ⁇ -4 Four of these receptors, 5-HT ⁇ -4 , have been characterized pharmacologically (Hoyer et al., 1994, Pharmacol. Rev. 46 (2): 157).
  • 5-HT receptors except the 5-HT 3 subtype (ion channel), belong to a superfamily of G-protein coupled receptors possessing seven transmembrane spanning sequences (Saudou & Hen, 1995, Adv. Pharmacol. 327; Peroutka & Howell, 1994, Neuropharmacol. 319). The following description of 5-HT receptors and ligands will be restricted to those that have been characterized pharmacologically (Chart 1).
  • Chart 1 5-HT receptors; their G-proteins, second messengers, agonists and antagonists
  • 5-HT IA receptors are encoded by intronless genes which form primary sequences between 365-422 amino acids in length and are found in a wide variety of central and peripheral tissues (Hoyer et al., 1994, Pharmacol. Rev. 46 (2): 157). The actions of agonists at 5-HT ⁇ receptors are mediated through a reduction in cellular cAMP by activation of an inhibitory G-protein (Gj/G 0 ) and reduction in adenylate cyclase activity (de Vivo & Maayani, 1986, J. Pharmacol. Exp. Ther. 248).
  • Gj/G 0 inhibitory G-protein
  • 5-HT ⁇ receptor In some tissues the 5-HT ⁇ receptor is directly coupled to membrane bound potassium (K + ) channel such that receptor activation leads to increased K + conductance and cellular hyperpolarization (Andrade et al., 1986).
  • K + membrane bound potassium
  • 5-HT IA receptors are distributed in a number of CNS areas involved in the modulation of erectile responses (Laporte et al., 1991, Eur. J. Pharmacol. 59) with particularly dense distribution in the hippocampus (Marcinkiewicz et al., 1984, Brain Res. 159). These receptors act as somatodendritic autoreceptors on 5-HT neurones, terminal heteroreceptors on non-5-HT neurones and as post-synaptic receptors.
  • 5-HT JA receptors Activation of any of these types of 5-HT JA receptors is believed to result in a reduction in neuronal activity which ultimately leads to a broad range of behavioral responses including hypothermia, hyperphagia and the 5-HT “behavioral syndrome” (de Montigny & Blier, 1992, Clin. Neuropharmacol. 610A).
  • Pharmacologically 5- HT IA receptors are marked by a high affinity for the agonist 8-OHDPAT and the antagonist WAY100635 (Hoyer et al., 1994, Pharmacol. Rev. 46 (2): 157).
  • Activation of 5-HT I B receptors induces changes in locomotion and temperature (Tricklebank et al., 1986, Neuropharmacol. 877) and it has recently been shown that mice lacking 5-HT IB receptors exhibit increased aggressive behavior (Ramboz et al., 1996, Behav. Brain Res. 305).
  • 5-HT JD receptors in humans have recently been classified as the species homologue (> 95% primary sequence homology but markedly different pharmacological profile) of the rodent 5-HT IB receptor (Hoyer et al., 1994, Pharmacol. Rev. 46 (2): 157).
  • the 5-HT ]D receptor is positively coupled to a stimulatory G-protein (G s/ ⁇ q ).
  • 5-HT ID receptors reside in a number of brain regions involved in the expression of erection with high densities in the nucleus accumbens, dorsal raphe, locus coeruleus, hippocampus and cortex (Hoyer et al., 1994, Pharmacol. Rev. 46 (2): 157).
  • 5-HT 2 receptors have been subclassified into three distinct subtypes (2A-2C) based on pharmacological and molecular evidence (Hoyer et al., 1994, Pharmacol. Rev. 46 (2): 157). 5-HT receptors share a large degree of overall homology (> 50 %), and even greater homology within the transmembrane spanning sequences (> 70 %), with positive coupling to G s /G ⁇ q and inositoltriphosphate (IP 3 ) turnover believed to be a common signal transduction pathway (Hoyer et al., 1994, Pharmacol. Rev. 46 (2): 157).
  • 5-HT A receptors are located centrally in the cortex, claustrum and basal ganglia and are believed to mediate the hallucinogenic effects and head shaking behaviors of the ergots and L-5-HTP respectively (Hoyer et al., 1994, Pharmacol. Rev. 46 (2): 157).
  • 5-HT A antagonists have been employed clinically for use in the treatment of hypertension (Barrett & Vanover, 1993, Psychopharmacol. 1) and are currently being explored for their efficacy in reducing the extrapyramidal side effects associated with treatments for Schizophrenia (Barrett & Vanover., 1993, Psychopharmacol. 1; Tricklebank, 1996, Behav. Brain Res. 15).
  • 5-HT 2B receptors and mRNA have been detected in central structures including the amygdala, septum, hypothalamus and cerebellum (Duxon et al., 1997, Neuropharmacol. 601).
  • the 5-HT 2B receptor is also distributed heavily in a wide variety of rat peripheral tissues, especially in the stomach fundus (Baxter et al, 1995, Trends Pharmacol. Sci. 105).
  • 5-HT 2B receptors mediate contraction of the stomach fundus but may also relax other vascular smooth muscle in a number of species through endothelium and NO dependent mechanisms (Baxter et al., 1995, Trends Pharmacol. Sci. 105).
  • 5-methoxytryptamine and ⁇ -methyl 5-HT are agonists which exhibit a high potency for 5-HT 2B receptors whereas yohimbine and rauwolscine (Baxter et al., 1995, Trends Pharmacol. Sci. 105) and the newly developed compound LY266097 exhibits high potency and selectivity in it's antagonist actions at this receptor subtype (Audia et al., 1996, J. Med. Chem. 2773).
  • 5-HT 2 c receptors are known to exist in extremely high density in the choroid plexus in a number of species including man (Pazos et al., 1987, Neuroscience. 97; Julius et al, 1988, Science. 558). Lower levels of this receptor subtype are found in cortex, hippocampus, striatum, substantia nigra and spinal cord (Hoyer et al., 1994, Pharmacol. Rev. 46 (2): 157; Helton et al., 1994, Neuroreport. 2617). At present there appears to be no evidence for the expression of 5-HT 2 c gene products within peripheral tissues (Helton et al., 1994, Neuroreport. 2617).
  • 5-HT c receptor is the first G-protein coupled receptor which has been shown to exhibit post-translational modification which results in 7 different splice variants, 4 of which have different pharmacological profiles in rat choroid plexus (Burns et al., 1997, Nature. 303).
  • 5-HT c receptors have been implicated in the regulation of cerebrospinal fluid production (Fisone et al., 1998, Pathways. Mol. Med. 258), migraine (Fozard & Gray, 1989, Arch. Pharmacol. 135) panic disorder (Lucki, 1992, Neurosci. Biobehav. Rev. 83), hyperthermia (Quested et al, 1996, Psychopharmacol.
  • the 5-HT 3 receptor is a cation permeable pentameric channel protein which is expressed in low levels in cortex, hippocampus and amygdala and at higher levels in peripheral nerves of the autonomic nervous system (Hoyer et al., 1994, Pharmacol. Rev. 46 (2): 157). At present there is evidence to suggest that this receptor may also exist in different forms as splice variants (Hope et al, 1993, Eur. J. Pharmacol. 187) and that a large degree of species variation exists in this receptors affinity for 5-HT 3 ligands (Fozard, 1989, Trends Pharmacol. Sci. 307).
  • 5-HT 3 receptor ligands will produce a wide variety of effects depending on the agonist or antagonist nature of the ligand and the basal tone of 5- HT receptor mediated activity (Eglen et al., 1993, J. Pharmacol. Exp. Ther. 535). Interest in this receptor subtype is intense due to the potential utility of 5-HT 3 receptor antagonists as antiemetics for cancer chemotherapy, cognitive enhancers, and antipsychotics (Fozard & Kalkman, 1992, Curr. Opin. Neurol. Neurosurg. 496). Antagonists include MDL72222, ondansetron and BRL46470A (Gargiulo et al, 1996, Neuropsychobiology. 189).
  • Agonists at 5-HT receptors are much more limited in number and utility.
  • 2-Methyl 5-HT, phenylbiguanide and chlorophenylbiguamde are all very potent in their binding to 5-HT 3 sites but usually show only partial agonist activity in functional screens in vitro and in vivo (Delagrange et al., 1996, Eur. J. Pharmacol. 195).
  • 5-HT4 receptors unlike 5-HT ⁇ A receptors, are thought to be positively coupled to adenylate cyclase through G s (Saudou & Hen, 1995, Adv. Pharmacol. 327) and have also been reported to alter neuronal calcium activated K + conductance (Andrade & Chaput, 1991, Science. 1261). Potent and selective 5-HT 4 ligands have been employed to map distributions of this receptor subtype to areas including the striatum, globus pallidus, substantia nigra, hippocampus and olfactory tubercle (Grossman et al., 1993, Br. J. Pharmacol. 618; Waeber et al., 1994, Neuropharmacol.
  • agonist action at this receptor subtype is associated with reduction in neuronal potassium current and both slow and rapid depolarization (Chaput et al., 1990, Eur. J. Pharmacol. 441), thus resulting in a functional increase in nerve output (Bockaert et al., 1990, Mol. Pharmacol. 408; Consolo et al., 1994, Neuroreport. 1230).
  • Peripherally 5-HT agonists cause contraction of a wide variety of vascular and non- vascular smooth muscles (Hedge & Eglen, 1996, FASEB J. 1398).
  • the most potent and selective agonists at 5-HT 4 receptors include SDZ205557 and RS39604 (Hedge et al, 1995, Br. J.
  • 5-HT 4 antagonists Based on the effects of agonists at central and peripheral sites 5-HT 4 antagonists have been developed and explored for their utility in the treatment of irritable bowel syndrome (Bockaert et al., 1990, Mol. Pharmacol. 408) and as antipsychotic agents, cognitive enhancers and anxiolytics (Steward et al., 1996, Br. J. Pharmacol. 55; Ge & Barnes, 1996).
  • Selective and potent antagonists at 5-HT, receptors include GR113808 and RS23597190 (Bockaert et al., 1990, Mol. Pharmacol. 408; Waeber et al., 1993, Neuroreport. 1239).
  • compositions preferably pharmaceutical compositions, which contain at least one compound of the present invention as set forth above, and at least one pharmaceutically acceptable carrier or diluent, where the compounds of the present invention demonstrate selective seretonin (5HT) receptor activity, including funtioning as either (i) a 5HT2c agonist and (simultaneously) a 5HT2a antagnoist, or (ii) simultaneously as a 5HT2c agonist, a 5HT2a antagonist, and a 5HTla agonist (weak).
  • 5HT seretonin
  • These compounds may be formulated into a composition in a form including salts, solvates, isolated enantiomers, isolated diastereomers, isolated tautomers, and mixtures thereof.
  • the composition may include, for example, water.
  • the composition is in the form of a tablet, and particularly a fast-release tablet for oral administration.
  • a fast-release tablet (having a rapid disintegration time) is desired in order to provide the patient with a rapid onset of enhanced sexual performance and/or increased libido and/or relief of sexual dysfunction.
  • a "fast-release" tablet will have a disintegration time of less than about one hour, preferably less than about 20 minutes, and more preferably less than about two or even one minutes.
  • a suitable fast-release tablet contains 40 mg of a compound of the present invention, 8 mg of silicon dioxide (NF), 4 mg of stearic acid (NF), 212 mg of lactose (NF), 120 mg of microcrystalline cellulose (NF) and 16 mg of croscarmellose sodium (NF).
  • a tablet containing these ingredients may be prepared by finely dividing and then mixing each ingredient together, then compressing the mixture into a tablet form. The tablet has a weight of about 400 mg. Other methods of mixing and tablet formulation will be readily apparent to one of ordinary skill in the art.
  • a tablet prepared by this method will typically have a hardness of 10.7 Kp, an average thickness of about 0.2 inches and an average disintegration time of about 45 minutes.
  • Disintegrant compounds such as croscarmellose sodium (NF) (available as Ac-Di-Sol from FMC Corporation), may be used to enhance the dissolution time of a formulation of the present invention.
  • Other disintegrants such as potato starch, ExplotabTM sodium starch glycolate, PolyplasdoneTM XL crospovidone NF, Starch 1500TM pregelatinized starch NF may be employed in the formulations of the present invention.
  • Each of U.S. Patent Nos. 5,731,339, 5,298,261 and 5,079,018 also describe formulations which demonstrate fast disintegration times, which may be employed to prepare a fast release formulation of the present invention.
  • Suitable disintegrants and methods for measuring disintegration time of tablets include Gissinger et al. "A Comparative Evaluation of the Properties of some Table Disintegrants” Drug Development and Industrial Pharmacy 6(5):511-536 (1980); and European Pharmacopeia 1980.
  • compositions of the present invention may be in any form which allows for the composition to be administered to a patient.
  • the composition may be in the form of a solid, liquid or gas (aerosol).
  • routes of administration include, without limitation, oral, topical, parenteral (e.g., sublingually or buccally), sublingual, rectal, vaginal, and intranasal.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal, intracavernous, intrameatal, intraurethral injection or infusion techniques.
  • Pharmaceutical composition of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • Compositions that will be administered to a patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of one or more compounds of the invention in aerosol form may hold a plurality of dosage units.
  • an excipient and/or binder may be present.
  • examples are sucrose, kaolin, glycerin, starch dextrins, sodium alginate, carboxymethylcellulose and ethyl cellulose.
  • Coloring and/or flavoring agents may be present.
  • a coating shell may be employed.
  • the composition may be in the form of a liquid, e.g., an elixir, syrup, solution, emulsion or suspension.
  • the liquid may be for oral administration or for delivery by injection, as two examples.
  • preferred composition contain, in addition to the inventive compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
  • a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
  • the liquid pharmaceutical compositions of the invention may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Physiological saline is a preferred adjuvant
  • a liquid compositions intended for either parenteral or oral administration should contain an amount of the inventive compound such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of a compound of the invention in the composition. When intended for oral administration, this amount may be varied to be between 0.1 and about 70% of the weight of the composition. Preferred oral compositions contain between about 4% and about 50% of the inventive compound. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 1% by weight of active compound.
  • the pharmaceutical composition may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base.
  • the base may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
  • Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device. Topical formulations may contain a concentration of the inventive compound of from about 0.1 to about 10% w/v (weight per unit volume).
  • the composition may be intended for rectal administration, in the form, e.g., of a suppository which will melt in the rectum and release the drug.
  • the composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient.
  • bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.
  • the compounds of the invention may be administered through use of insert(s), bead(s), timed-release formulation(s), patch(es) or fast-release formulation(s).
  • the optimal dosage of the compound(s) of the invention may depend on the weight and physical condition of the patient; on the severity and longevity of the sexual dysfunction (when the goal is to treat sexual dysfunction); on the particular form of the active ingredient, the manner of administration and the composition employed. It is to be understood that use of a compound of the invention in a chemotherapy can involve such a compound being bound to an agent, for example, a monoclonal or polyclonal antibody, a protein or a liposome, which assist the delivery of said compound.
  • an agent for example, a monoclonal or polyclonal antibody, a protein or a liposome, which assist the delivery of said compound.
  • the invention relates further to a pharmaceutical or veterinary composition
  • a pharmaceutical or veterinary composition comprising an effective amount of a compound of the invention in association with a carrier.
  • the present invention is directed to the use of a compound of the invention (having a receptor profile as identified above, and which includes physiologically acceptable salts and hydrates), for the manufacture of a medicament for treating, relieving or preventing the effects of sexual dysfunction.
  • the compound(s) of the invention may be used for the manufacture of a medicament for treating, relieving or preventing the effects of male sexual dysfunction, preferably erectile inadequacy and inhibited male orgasm, especially erectile inadequacy.
  • the the compound(s) of the invention may also be used for the manufacture of a medicament for treating, relieving or preventing the effects of female sexual dysfunction, preferably sexual arousal disorder and inhibited femal orgasm, especially sexual arousal disorder.
  • the present invention provides a method for the treatment of a male or female patient suffering from sexual dysfunction, or a method to prevent sexual dysfunction in a patient (having, for example, a history of sexual dysfunction) comprising the administration thereto of a therapeutically or prophylactically effective amount of a compound(s) of the invention or a composition including same, as provided above.
  • the sexual dysfunction may be, for example, male erectile dysfunction or impotence.
  • a patient that cannot obtain an erection may be treated according to the present invention, while a patient that cannot maintain an erection may receive a prophylactic dose of a compound of the invention in order to prevent premature loss of an erection.
  • the present invention provides a method for increasing the libido of a male or female patient comprising the administration thereto of a therapeutically effective amount of a compound(s) of the invention or a composition including same, as provided above.
  • the present invention provides a method for enhancing the sexual performance of a male or female patient that is not necessarily exhibiting symptoms of sexual dysfunction, comprising administering to the patient in need thereof a therapeutically or prophylactically effective amount of a compound of the invention, or a composition including same, as provided above.
  • Enhanced sexual performance occurs when there is an increase in the type of behavior that is typically associated with the patient's sexual activity or interest in sexual activity.
  • Enhancement of sexual performance may result in, e.g., a pro- erectile response in the patient, or an improvement in erectile function such as any increase in the ability of the patient maintain an erection, induce or improve ejaculation (e.g., have multiple ejaculations within a shortened period of time), or induce or improve orgasm.
  • Specific examples of enhancements in sexual performance are described in connection with the pharmacological testing of compounds and compositions of the present invention, as set forth herein.
  • therapeutically effective amount refers to an amount which is effective, upon single or multiple dose administration to the patient, to enhance the libido and/or sexual performance of the patient receiving the compound or a composition containing the compound as provided above. Such an amount may serve to treat a sexual dysfunction, e.g., impotence in males, and/or to enhance the sexual desire and/or sexual performance of a patient without a sexual dysfunction.
  • the therapeutically effective amount may be administered to, for example, a bull, to promote increased semen ejaculation, where the ejaculated semen is collected and stored for use as it is needed to impregnate female cows in promotion of a breeding program. Increased sexual ejaculation is an example of enhanced sexual performance according to the present invention.
  • a therapeutically or prophylactically effective amount of a substituted acetic acid derivative of the invention is expected to vary from about 0.01 milligram per kilogram of body weight per day (mg/kg/day) to about 200 mg/kg/day. Preferred amounts are expected to vary from about 0.5 to about 80 mg/kg/day.
  • a pharmaceutical composition containing a compound(s) of the invention may contain between 0.01 and 1% by weight of the active ingredient, and between about 5 and 10% by weight glucose in order to increase the osmolarity of the solution.
  • Two illustrative compositions are (1) 5 mg/mL of a compound(s) of the invention and distilled water in 100 mL total volume, and (2) 5 mg/mL of a compound(s) of the invention, 25 mg/mL glucose, and distilled water in 100 mL total volume.
  • a compound of the invention can be administered in any form or mode which makes the compound bioavailable in effective amounts, including oral, aerosol, and parenteral routes.
  • compounds of the invention can be administered orally, by aerosolization, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, topically, and the like.
  • the compounds of the invention may be administered by direct injection into, e.g., the corpus cavernosa (intracavernously).
  • the compounds of the invention may be administered intraurethrally (e.g., via an intraurethral catheter).
  • the compounds of the invention may be administered topically, e.g., directly to the penis.
  • the compounds may be administered intrameatally.
  • Oral or aerosol administration is generally preferred.
  • One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition, and other relevant circumstances. See, e.g., Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990).
  • the compounds can be administered alone or in the form of a pharmaceutical composition in combination with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the solubility and chemical properties of the compound selected, the chosen route of administration, and standard pharmaceutical practice.
  • the present invention provides compositions comprising a compound(s) of the invention in admixture or otherwise in association with one or more inert carriers.
  • These compositions are useful, for example, as assay standards, as convenient means of making bulk shipments, or as pharmaceutical compositions.
  • An assayable amount of a compound of the invention is an amount which is readily measurable by standard assay procedures and techniques as are well known and appreciated by those skilled in the art. Assayable amounts of a compound of the invention will generally vary from about 0.001% to about 75% of the composition by weight.
  • Inert carriers can be any material which does not degrade or otherwise covalently react with a compound of the invention.
  • Suitable inert carriers are water; aqueous buffers, such as those which are generally useful in High Performance Liquid Chromatography (HPLC) analysis; organic solvents, such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable carriers or excipients.
  • HPLC High Performance Liquid Chromatography
  • compositions comprising a therapeutically effective amount of a compound(s) of the invention, in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art.
  • the carrier or excipient may be a solid, semi-solid, or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art.
  • the pharmaceutical composition may be adapted for oral, parenteral, or topical use and may be administered to the patient in the form of tablets, capsules, solution, suspensions, or the like.
  • the compounds of the present invention may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • These preparations should preferably contain at least 4% of the compound of the invention as an active ingredient, but this amount may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit.
  • the amount of the compound present in compositions is such that a suitable dosage will be obtained.
  • the tablets, pills, capsules and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.
  • a liquid carrier such as polyethylene glycol or a fatty oil.
  • dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings.
  • tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
  • a syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • the compounds of the present invention may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of a compound of the invention, but this amount may be varied to be between 0.1 and about 50% of the weight thereof. The amount of the inventive compound present in such compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 1% by weight of active compound.
  • the compounds of the present invention may also be administered by aerosol.
  • aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages.
  • Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient. Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, spacers and the like, which together may form a kit. Preferred aerosols are able to be determined by one skilled in the art.
  • the compounds of this invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment or gel base.
  • the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
  • Topical formulations may contain a concentration of the inventive compound of from about 0.1 to about 10% w/v (weight per unit volume).
  • the solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Physiological saline is a preferred carrier or diluent.
  • the compound(s) of the invention may be combined with one or more known pharmacological agents used in the treatment and/or prevention of sexual dysfunction and/or known to enhance the libido and/or sexual performance of a patient receiving the pharmacological agents.
  • the following examples are offered by way of illustration and not by way of limitation.
  • 2-Naphthylacetic acid (1.86 g, 10 mmol) was refluxed in thionyl chloride (10 mL) for 1 h. After stirring at room temperature for a further 1.5 h, the thionyl chloride was removed in vacuo (using 1 x 10 mL and 2 x 5 mL CC1 4 ). The residue was dissolved in dichloromethane (15 mL). Then the acid chloride solution was added via cannula to a cooled solution (ice bath) of tert-butyl 1-piperazine carboxylate (1.86 g, 10 mmol) and triethylamine (1.4 mL, 10 mmol) in dichloromethane (15 mL) under nitrogen.
  • the reaction mixture was diluted with dichloromethane (60 mL) and washed with 1M HC1 aqueous solution (50 mL), water (30 mL), 1M sodium bicarbonate aqueous solution (50 mL) and water (30 mL).
  • the organic layer was collected, dried over sodium sulfate and concentrated in vacuo to yield the crude intermediate carbamate suitable for the next step without any further purification.
  • the above carbamate dissolved in ethyl acetate (100 mL) was treated with HCI saturated ethyl acetate solution (50 mL). After a few minutes a precipitate was formed and the reaction mixture was stirred for another 4 hours in order to complete the reaction. The yellow precipitate was collected and recrystallized from ethanol to yield 1.98 g of the title compound.
  • NMR analyses protonon and C-13
  • mass spectroscopic analysis of the product are consistent with the structure indicated.
  • binding affinities of compounds of the present invention for the different subtypes of serotonin receptors (5-HT) can be performed using with some modifications, standard methods reported in the literature.
  • 5-HT IA (Hoyer et al. 1985, Eur. J. Pharmacol. 13; Schoeffter et al. 1989, Naunyn-Schmiedberg Arch. Pharmacol. 135).
  • Receptor Source Human recombinant expressed in HeLa cells.
  • Radioligand [ 3 H]-8-OH-DPAT (100 Ci/mmol); Final ligand concentration - [0.25 nM].
  • Incubation Conditions Reactions are carried out in 50 mM TRIS-HCl (pH 7.4) containing 10 mM MgCl, 0.5 mM EDTA, and 0.1% Ascorbic acid at 25°C for 60 minutes. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound with the cloned 5-HT JA binding site.
  • 5-HT IB (Hoyer et al., 1985; Eur. J. Pharmacol. 13; Schoeffter et al. 1989, Naunyn-Schmiedberg Arch. Pharmacol. 135).
  • Receptor Source Rat striatal membranes.
  • Radioligand [ 125 l]-Iodocyanopindolol (2200 Ci/mmol); Final ligand concentration - [0.15 nM].
  • Incubation Conditions Reactions are carried out in 50 mM TRIS-HCl (pH 7.4) containing 60 ⁇ M (-) isoproterenol at 37°C for 60 minutes. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound with the 5-HT binding site.
  • Receptor Source Bovine striatal membranes
  • Radioligand [3H]-5- Carboxamidotryptamine (5-CT) (20-70 Ci/mmol). Final ligand concentration - [0.75 nM].
  • Incubation Conditions Reactions are carried out in 50 mM TRIS-HCl (pH 7.7) containing 4mM CaCl 2 , 100 nM 8-OH-DPAT, 100 nM Mesulergine, 10 ⁇ M pargyline and 0.1% ascorbic acid at 25°C for 60 minutes. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound with the 5-HT JD binding site.
  • 5-HT 2A (Leysen et al., 1982, Mol. Pharmacol. 301; Martin et al.,
  • Receptor Source Rat cortical membranes.
  • Radioligand [3H] Ketanserin (60-90 Ci/mmol). Final ligand concentration - [l.OnM].
  • Incubation Conditions Reactions are carried out in 50 mM TRIS-HCl (pH 7.6) at 37°C for 60 minutes. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound with the 5-HT 2 binding site.
  • 5-HT 2C (Pazos et al., 1985b, Eur. J. Pharmacol. 539; Hoyer et al., 1985, Eur. J. Pharmacol. 13).
  • Receptor Source Pig choroid plexus membranes.
  • Radioligand [3H] Mesulgerine (50-60 Ci/mmol). Final ligand concentration - [1.0 nM].
  • Incubation Conditions Reactions are carried out in 50 mM TRIS-HCl (pH 7.7) containing 4mM CaCl 2 and 0.1% ascorbic acid at 37°C for 60 minutes. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound with the 5-HT 2 c binding site.
  • 5-HT 3 (Lummis et al., 1990, Eur. J. Pharmacol. 223; Hoyer et al, 1988, Mol. Pharmacol. 303; Tyers, 1991, Therapie, 431).
  • Receptor Source N1E- 115 cells.
  • Radioligand [3H]-GR65630 (30-70 Ci/mmol). Final ligand concentration - [0.35nM].
  • Incubation Conditions Reactions are carried out in 20 mM HEPES (pH 7.4) containing 150 mM NaCl at 25°C for 60 minutes. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound with the 5-HT 3 binding site.
  • Table 1 shows the effects of Compound 1 (10 "5 M) and Compound 7 (10 "5 M) on the binding of specific radioligands to their respective 5-HT subtype receptors as indicated below.
  • Data are expressed as the % inhibition of radioligand binding by the test compound at the concentrations used. NS denotes results are less than 20% and are generally considered to be non-significant for these assays.
  • mice were injected via an intraperitoneal (i.p.) route with saline or test drug and placed individually in clear Plexiglas® cages of 45 x 25 x 25 cm for behavioral observation. Erection was recorded for test animals exhibiting an abrupt upright posturing motion with repeated licking of the engorged penis. Rats housed in groups of six were treated with saline or Compound 1 (2.0-64.0 mg/kg) and, 5 minutes later, observed for the appearance of erection and the latency to first erection over 90 minutes. Rats housed in pairs were treated with saline,
  • Compound 1 enhanced erection during 90 minutes of observation in a dose-dependent manner.
  • a clearly defined maximum of 7.7 ⁇ 0.4 erections was elicited at a dose of 16 mg/kg.
  • Saline treated rats exhibited 1.2 ⁇ 0.4 erections over 90 minutes of observation ( Figure 1).
  • the time to the appearance of the first erection was reduced in a dose-dependent manner.
  • a minimal latency to first erection of 654 ⁇ 108 seconds also occurred at a dose of 16 mg/kg ( Figure 1).
  • At the highest dose tested the number of erections was significantly increased as compared to saline treated animals whereas the time to first erection was significantly reduced compared to saline controls. All animals (100%) treated with Compound 1 exhibited erection whereas only 60% of saline treated animals exhibited erection ( Figure 1 ).
  • Diagram 1 Structural formulae of some of the compounds tested in this study.
  • m-CPP and TFMPP elicited maximal effects of 2.6 ⁇ 0.2 and 1.8 ⁇ 0.3 erections at doses of 0.75 and 1.0 mg/kg respectively (p ⁇ 0.01 vs. saline; Figure 3).
  • the erection enhancing action of Compound 1 is dose-related with significant increases in erection at all of the doses tested (2.0-32.0 mg/kg).
  • the erectogenic actions of Compound 2 were significant at all but the lowest dose tested (2.0 mg/kg).
  • Other related compounds showed varying degrees of pro-erectile activity.
  • the non- piperazine analog, Compound 3 failed to increase the appearance of erection, as compared to saline treated rats, at any of the doses tested (2.0-32.0 mg kg) (p > 0.15 vs. saline; Figure 2).
  • 1-NP a non-substituted 1 -naphthyl arylpiperazine, failed to elicit erection at any of the doses tested but did significantly reduce erection at the highest dose tested (10.0 mg kg) (p ⁇ 0.5 vs. saline; Figure 3).
  • Compound 5 was without significant effect on spontaneous erectile responses at any of the doses tested (0.1-10.0 mg/kg) (p > 0.15 vs. saline; Figure 4). A number of similar experiments were carried out to demonstrate the pro-erectile property of some other compounds of the invention. Results of these experiments are briefly described below.
  • the average latency to the first erection was 252 seconds.
  • Compound 1 produced a dose-dependent increase in grade 1 penile erections (Table 2). There was a dose-related trend for an increase in the number of grade 2 and grade 3 responses (Table 2). Compound 1 produced a dose-related trend for increase in pursed-lip gesturing which reached significance at a dose of 10.0 mg/kg (Table 3). Table 2
  • Table 2 shows the effects of Compound 1 on erectile responses in male primates observed in isolation. Data are expressed as mean ⁇ SEM for 6 test animals. Penile responses were scored every 10 seconds for 1 hour according to the following scale: grade 0, penile region visible but glans penis not visible; grade 1, glans penis clearly visible; grade 2, penis extended but not fully erect; grade 3, erect penis (less than 90 ° angle between penis and animals trunk); grade 4, erection with masturbation and grade 5, erection with masturbation and ejaculation. An asterisk indicates significant difference from saline as determined by repeated measures ANOVA and Dunnett's test for multiple comparisons (p ⁇ 0.05).
  • Table 3 shows the effects of Compound 1 on affiliative behaviors in male primates observed in isolation. Data are expressed as mean ⁇ SEM for 6 test animals. Pursed-lip gestures and yawning are described as the absolute number of events during 60 minutes of observation. An asterisk indicates significant difference from saline as determined by repeated measures ANOVA and Dunnett's test for multiple comparisons (p ⁇ 0.05).
  • Table 4 shows the effects of Compound 1 and other related compounds on penile and affiliative behavior responses in male primates observed in a paired setting. Data are expressed as the percentage of test animals having a particular grade of penile response. Penile responses were scored every 10 seconds for 1 hour according to the following scale: grade 0, penile region visible but glans penis not visible; grade 1, glans penis clearly visible; grade 2, penis extended but not fully erect; grade 3, erect penis (less than 90 ° angle between penis and animals trunk); grade 4, erection with masturbation and grade 5, erection with masturbation and ejaculation. Affiliative behavioral responses were scored as the absolute number of events during 60 minutes of observation. EXAMPLE 8
  • the 5-HT synthesis inhibitor (pCPA) was used to destroy pre-synaptic serotonergic inputs.
  • NAN-190 (0.02-2.0 mg/kg) 30 minutes prior to i.p. injection with a maximally effective erectogenic dose of Compound 1 (16 mg/kg). Observations of erectile responses were carried out for 30 minutes as described previously (Example 6).
  • 5-HT 2A and 5-HT 2 c receptors respond differently to acute versus chronic treatment with agonists and antagonists (Aulakh et al., 1994, J. Pharmacol. Expl Ther. 127; Mazzola-Pomietto et al., 1996). Most notably, hyperthermia induced by the 5-HT 2A/ c agonist DOI and the 5-HT c agonist m-CPP were significantly reduced by mianserin and ritanserin administered acutely.
  • 5-HT 2 c receptor activation and antagonism have been elucidated which also help to confirm the role of 5-HT c receptors in a given drugs actions (Newton et al., 1996).
  • 5-HT 2 c interaction A high dose of ritanserin (3.0 mg/kg) administered daily for 10 days significantly reduced the erection enhancing actions of Compound 1 to a level which was not significantly different from saline treated animals ( Figure 5; p > 0.05). Erectile responses in the presence of a high dose of ritanserin were significantly less than erectile responses in vehicle treated animals.
  • Results obtained with the 5-HT synthesis inhibitor pCPA provide support for a direct action on post-synaptic 5-HT 2 c receptors.
  • An indirect action mediated by release of 5-HT maybe excluded on the grounds that 1) erections produced by the 5-HT releaser fenfluramine are significantly reduced in animals pre- treated with pCPA (Maeda et al., 1994b, Brain Res. 181 ; ) and 2) pCPA fails to inhibit the erection enhancing actions of compounds having documented affinity and activity at 5-HT 2 c receptors (Protais et al., 1995, Psychopharmacol. 376).
  • 5-HT IA receptor interaction From the available literature, the role of 5-HTI A receptors in erection is not well understood. While it is clear that 5- HT IA receptor agonists (full) inhibit erection mediated by a number of different mechanisms the same simplicity is not apparent for the actions of 5-HTI A antagonists on erectile responses. Simon et al. (1993, Neuroreport.
  • tertatolol a ⁇ -adrenergic receptor antagonist having high affinity antagonist properties at 5-HT IA receptors (Prisco et al., 1993), enhances erection induced by the 5-HT re- uptake inhibitors fenfluramine and fluoxetine and the 5-HT 2C agonist m-CPP.
  • labetolol a ⁇ -adrenergic receptor antagonist having very low affinity for 5-HT IA receptors, but also having significant ⁇ -adrenergic receptor antagonist actions, inhibited erection produced by fluoxetine and m-CPP but not fenfluramine.
  • Protais et al. (1995) have demonstrated that tertatolol does not enhance m-CPP induced erection directly but does reverse the inhibitory actions of the strong 5-HTj A agonists 8- OHDPAT and S14506.
  • NAN-190 a compound having both 5-HT ⁇ A and -adrenergic antagonist actions (Gobert et al., 1995. J. Pharmacol. Exp. Ther. 1032) was studied. NAN-190 dose-dependently inhibited the erection enhancing actions of Compound 1, which is in agreement with the results obtained with pindolol. Support for a mechanism involving differential actions at 5-HT ⁇ A receptors comes from the observation that NAN-190 does not act as an antagonist at ⁇ -adrenergic receptors (Millan et al., 1995, , J. Pharmacol. Exp. Therap.
  • NAN-190 is an effective ⁇ i receptor antagonist and it is therefore possible that it is these properties which produce its inhibitory actions on the Compound 1 induced erection responses.
  • the above examples support the findings that the erection enhancing actions of Compound 1 are induced by activation of 5-HT 2 c receptors at post-synaptic sites within the CNS.
  • Grooming was scored as being either penile or non-penile according to Sachs et al. (1988, The physiology of reproduction. 1393); with penile grooming being restricted to the genital region and non-penile grooming being any grooming bouts at any region other than the genitalia. Movement was scored as the number of rears during 1 hour and the total number of quadrant crosses during 6 two minute observation periods at 10 minute intervals. Rectal temperature was recorded by thermometer before, and 60 minutes after, saline or drug administration. Results
  • Compound 1 significantly increased erection and ejaculation from 0.8 ⁇ 0.3 erections and 0.3 ⁇ 0.1 ejaculations in saline treated animals to 5.1 ⁇ 0.6 erections and 1.5 ⁇ 0.3 ejaculations (Figure 8).
  • m-CPP (0.75 mg/kg) and TFMPP (1.0 mg/kg) induced 2.0 ⁇ 0.2 and 1.5 ⁇ 0.3 erections respectively, far fewer erections than Compound 1, and failed to induce ejaculation in any of the animals tested (Figure 8).
  • Compound 1 increased grooming of the genital region from 7.5 ⁇ 0.8 bouts in saline treated animals to 12.5 ⁇ 1.7 bouts.
  • m-CPP and TFMPP both reduced genital grooming to 4.8 ⁇ 1.0 and 2.6 ⁇ 0.5 bouts respectively (Figure 10).
  • Non-genital grooming was also significantly reduced by m-CPP and TFMPP to 8.0 ⁇ 1.0 and 7.3 ⁇ 1.2 bouts respectively from a value of 20.7 ⁇ 2.0 bouts in saline controls.
  • Compound 1 failed to significantly alter non-genital grooming bouts with 21.5 ⁇ 3.0 bouts recorded (Figure 10).
  • Example 9 Compound 1 was shown to posses markedly different, and stimulatory actions on seminal emission compared to the erectogenic compounds m-CPP and TFMPP in freely moving rats. These actions may be of benefit, from a procreative perspective, as a potential pharmacotherapy for erectile dysfunction. From a prosexual perspective arousal and performance are important aspects of sexual behavior (Schiavi & Segraves, 1995, Psychiatr. Clin. North Am. 7).
  • the selective 5-HT JA agonist 8-OHDPAT improves copulatory performance in rats through reduction in ejaculatory threshold (Glaser et al., 1991, Brain 5HT1A receptors: behavioral and neurochemical pharmacology. 106; Johanssen et al., 1991, Eur. J. Pharmacol. 81) and, is thought to enhance arousal through a reduction in latency to mount, intromission and resumption of copulation after ejaculation (Ahlenius & Larsson, 1991b, Brain 5-HTA1 receptors: behavioral and neurochemical pharmacology. 185).
  • 8-OHDPAT is known to inhibit erectile responses in most species studied to date (Schnur et al., 1989, Physiol. Behav. 897; Pomerantz et al., 1993a,Eur. J. Pharmacol. 227).
  • a rat model of copulatory performance was used to determine its effects on appetitive and consumptive patterns of sexual behavior.
  • Male and female Long-Evans rats (500-650 g) housed under 12 hour reverse light cycle were used in this study.
  • Male rats were injected with saline or Compound 1 (1.5-15.0 mg/kg) 20 minutes prior to being paired with an ovariectomized and primed (10 ⁇ g estradiol benzoate and 500 ⁇ g progesterone at 48 hours and 4 hours prior to experiment respectively) female (Tanco et al., 1993, Experientia. 238).
  • Compound 1 failed to significantly alter the post- ejaculatory interval at any of the doses tested despite a dose related trend for reduction in mean differences compared to controls.
  • Table 5 shows the effects of Compound 1 (1.5-15.0 mg/kg) on copulatory behaviour in male rats. Data are expressed as mean ⁇ SEM for 15 animals at each dose with a 15 animal saline treated control group at each dose. Latency values for mount, intromission, ejaculation and post-ejaculatory interval are in seconds whereas mounts intromissions and ejaculations are number per 30 minutes observation. An asterisk indicates significant difference compared to saline control (p ⁇ 0.05; t-test).
  • Compound 1 enhanced copulatory performance by reducing the number of intromissions preceding ejaculation and by increasing the number of ejaculations during 30 minutes of observation. This profile is distinctly different from the copulatory behavior profiles of the erectogenic piperazine 5-HT agonists m-CPP and TFMPP. Both of the latter compounds have been shown to reduce the proportion of animals exhibiting mounting behavior and increase the number of mounts and intromissions preceding ejaculation (Fernandez-Guasti et al., 1989, Pharmacol. Biochem. Behav. 811; Mendelson & Gorzalka, 1990).
  • TFMPP which, at maximally effective erectogenic doses (1.0 mg/kg), completely suppresses copulatory behavior (Fernandez-Guasti et al., 1989, Pharmacol. Biochem. Behav. 811).
  • m-CPP on the other hand has a less marked effect on mounts and intromissions but does reduce the percentage of animals achieving ejaculation significantly at maximally effective erectogenic doses (Fernandez-Guasti et al., 1989, Pharmacol. Biochem. Behav. 811).
  • the selective 5-HT IA agonist 8-OHDPAT reduces mounts and intromissions preceding ejaculation and reduces ejaculation latency (Fernandez-Guasti & Rodriguez-Manzo, 1992; Fernandez-Guasti et al., 1992).
  • 5-HT 2A/2 B antagonism would have to be co-expressed with 5-HT 2 c agonist actions as 5-HT 2A and 5-HT 2 B antagonists are not known to elicit erections on their own (Berendsen & Broekkamp, 1987, Eur. J. 279).
  • 5-HT 2A antagonists have been shown to unmask the erection enhancing actions of mixed 5-HT 2A/2C agonists (Berendsen & Broekkamp, 1991, Psychopharmacol. 219).
  • Example 10 it was shown that Compound 1 enhanced copulatory performance as measured by a reduction of mounts and intromissions prior to ejaculation and elevated the number of ejaculations per test series as compared to saline treated animals. However Compound 1 failed to promote sexual response variables indicative of arousal state (mount and intromission latency). It has been proposed that desire or motivational aspects of sexual function may be different than those of arousal and may be assessed through employment of sexually exhausted male rats (Karen & Barfield, 1975, J. Comp. Physiol. Psychol. 693). To better understand the apparent beneficial effects of Compound 1 on copulatory performance of male rats, Compound 1 was administered to sexually exhausted rats in order to assess its effects on motivational aspects of copulation.
  • Behavioral responses were measured as proportions of animals exhibiting mount, intromission, ejaculation and resumption of copulation after the first ejaculation. The latencies to mount, intromission, ejaculation and resumption of copulation after the first ejaculation, and the number of mounts and intromissions preceding ejaculation were recorded.
  • Compound 1 and 8-OHDPAT did not have disparate effects on arousal variables in sexually exhausted rats with mount and intromission latencies of 61 ⁇ 10 seconds and 134 ⁇ 21 seconds and, 65 ⁇ 5 seconds and 99 ⁇ 12 seconds for Compound 1 and 8-OHDPAT respectively (p> 0.70 and p > 0.10 for mount and intromission latencies respectively). Latency to first ejaculation was significantly shorter at 384 ⁇ 37 seconds in 8-OHDPAT treated sexually exhausted rats compared to 825 ⁇ 108 seconds in exhausted rats receiving Compound 1. 8-OHDPAT (5/5) was more effective than Compound 1 (3/5) in stimulating rats to initiate copulation after the first ejaculatory sequence but this effect was not significant.
  • 8-OHDPAT treated rats also ejaculated after fewer mounts and intromissions than rats treated with Compound 1.
  • Mounts and intromissions preceding ejaculation were 0.7 ⁇ 0.2 mounts and 5.5 ⁇ 1.3 intromission for 8-OHDPAT treated rats whereas Compound 1 treated rats exhibited 9.4 ⁇ 1.3 mounts and 15.2 ⁇ 1.6 intromissions prior to ejaculation (p ⁇ .001 and p ⁇ .002 for mounts and intromissions respectively).
  • Post-ejaculatory intervals were 637 (492-762) (range) seconds and 1030 ⁇ 129 seconds for sexually exhausted rats receiving Compound 1 and 8-OHDPAT respectively.
  • Results from this Example represent the first report of the effects of an erectogenic arylpiperazine on copulatory function in exhausted male rats.
  • Compound 1 significantly increased the number of sexually exhausted rats engaging in copulation and also significantly increased the numbers of these rats attaining ejaculation.
  • Compound 1 has positive effects on motivational and desire aspects of copulatory function similar to, but less marked than, 8-OHDPAT. While no attempt was made to determine the nature of the stimulus effect of Compound 1 on copulation in sexually exhausted rats, the compound space required for the stimulus effects of a chemically diverse group of compounds may be expanded to include at least one form of arylpiperazine.
  • Rat basilar artery was obtained, prepared and treated as described for experiments with rat aorta. However in this series of experiments only two high concentrations of Compound 1 were tested against the contractile responses of 5-HT. Tissue preparations were incubated with saline or Compound 1 (10 ⁇ 5 or 10 "4 M) for 5 minutes prior to construction of concentration-response curves for increasing concentrations of 5-HT (3 x 10 " to 10 M). Data was calculated as the percentage of the maximal response to agonist in each tissue.
  • Isolated rat stomach fundus Male SD rats (500-700 g) were sacrificed with CO 2 and the fundus portion of the stomach was removed and prepared as described previously (Clineschmidt et al., 1985, J. Pharmacol. Exp.
  • stomach from each animal was divided into two strips of equal length and width. Incisions were made perpendicular to the vertical plane of the muscle strip such that contractile force was transmitted along the vertical axis of the tissue. Tissues were prepared and allowed to equilibrate as described above.
  • Preparations were challenged with 5-HT (10 "6 M) three times at hourly intervals with 5 exchanges of bathing fluid between tests.
  • concentration-response curves were constructed for the contractile actions of 5-HT (10 "10 to 10 "4 M), Compound 1 (10 "10 to 10 “4 M) and m- CPP (10 "10 to 10 "4 M). Contractile responses to the three drugs were calculated as the percent of the maximal effect of the third challenge with 5-HT (10 "6 M).
  • Table 7 shows the effects of Compound 1 on the concentration- response characteristics of KCl mediated contraction of isolated rat aorta. EC 50 and slope values were derived from curve fits to individual concentration-response curves. Data are expressed as the mean ⁇ SEM for 6 experiments, t-test indicates comparisons for significant differences between treatment groups for the variable indicated.
  • Table 8 shows the effects of Compound 1 on the concentration- response characteristics of NA mediated contraction of isolated rat aorta. EC 50 and slope values were derived from curve fits to individual concentration-response curves. Data are expressed as the mean ⁇ SEM for 4 experiments. ANOVA indicates comparisons for significant differences between treatment groups for the variable indicated.
  • Compound 1 produced a concentration-dependent rightward shift of the concentration-response curve ( Figure 13).
  • Figure 13 At lower concentrations Compound 1 shifted the EC 50 for 5-HT mediated contraction, in a non-significant trend, without affecting the slope of the relationship or maximal responses to 5-HT.
  • Compound 1 significantly increased the EC 50 for 5-HT mediated contraction without affecting the slope and maximal responses of the tissue preparations to 5-HT (Table 9).
  • Table 9 shows the effects of Compound 1 on the concentration- response characteristics of 5-HT mediated contraction of isolated rat aorta. EC 50 and slope values were derived from curve fits to individual concentration-response curves. Data are expressed as the mean ⁇ SEM for 5-7 experiments. ANOVA indicates comparisons for significant differences between treatment groups for the variable indicated. An asterisk indicates a significant difference from saline controls.
  • Compound 1 had complex actions on rabbit basilar artery. At a concentration of 10 ⁇ M Compound 1 failed to shift the EC 50 for 5-HT mediated contraction and also failed to alter the slope of the 5-HT concentration-response relationship. However at a concentration of 100 ⁇ M Compound 1 significantly increased the EC 50 for 5-HT mediated contraction and reduced the slope of the concentration-response curve without affecting the maximal response to 5-HT ( Figure 14; Table 10).
  • Table 10 shows the effects of Compound 1 and saline on the concentration-response characteristics of 5-HT mediated contraction of the isolated rat basilar artery.
  • Maximal effect (g) is the maximum tension developed in grams whereas EC 50 and slope are the curve-fit locator and descriptor as derived from averages of curve-fits to individual concentration-response curves. Data are expressed as the mean ⁇ SEM for 4-8 strips. An asterisk indicates significant differences between treatment groups for the variable indicated (p ⁇ 0.05 by ANOVA).
  • m-CPP behaved as a partial agonist with less maximal efficacy but similar potency to that of 5-HT ( Figure 19, Table 11).
  • Compound 1 failed to elicit contraction in a manner consistent with an agonist profile in this tissue.
  • Compound 1 exhibited markedly less maximal efficacy and reduced potency compared to both 5-HT and m-CPP (Table 11).
  • Table 11 shows the contractile effects of serotonin (5-HT), m- Chlorophenylpiperazine (m-CPP) and Compound 1 on isolated rat stomach fundus.
  • Pre-drug maximal responses to the final test dose of 5-HT (1.0 ⁇ M) were not significantly different at 6.1 ⁇ 0.6 g, 5.7 ⁇ 0.4 g and 5.4 ⁇ 0.6 g for 5-HT, Compound 1 and m-CPP respectively (p > 0.70 by ANOVA).
  • An asterisk indicates a significant difference from the 5-HT treated tissues and + indicates a significant difference from m-CPP treated tissues (ANOVA and Dunnett's test; p ⁇ 0.05).
  • Table 12 shows the effects of increasing concentrations of Compound 1 and 1-naphthylpiperazine (1-NP) on 5-HT mediated contraction of the rat stomach fundus. Maximal pre-drug responses for determination of % maximal effect for 5-HT in the presence of saline (6.1 ⁇ 0.4 g), Compound 1 (3.0 ⁇ 0.5, 4.3 ⁇ 0.3, 3.9 ⁇ 0.7 g) and 1-NP (4.0 ⁇ 0.8, 4.2 ⁇ 0.6 g) were not significantly different (p > 0.05 by ANOVA). pD 2 was calculated as the negative logarithm of the EC 50 from individual curve fits. Data are expressed as the mean ⁇ SEM for 4-12 strips for the variable indicated in the table.
  • Rat basilar artery is commonly used as a preparation for the bioassay of 5-HT ligands (Skingle et al., 1996, Behav. Brain Res. 157). Numerous reports have suggested that multiple 5-HT receptor subtypes mediated contraction in the basilar artery of a number of species (Connor et al., 1989; Frenken, 1989; Gaw et al., 1990). The low concentration effect is believed to be mediated by a 5-HT ⁇ type receptor (Parsons & Whalley, 1989; Ohnuki & Ogawa, 1997) whereas at higher concentrations maximal responses are obtained with compounds having agonist activity at 5-HT 2 receptors, but not 5-HT JD/IB receptors (Martin et al., 1997, Br. J. Pharmacol.
  • a change in the slope of the concentration-response relationship for 5-HT might be expected in the presence of an antagonist that failed to inhibit the low concentration 5-HT ⁇ component but displaced the 5-HT 2 mediated high concentration component. Conversely a compound having antagonist actions at both the 5-HT) and 5-HT 2 receptors would be expected to shift the curve in parallel such that no change in slope would be observed.
  • Compound 1 also failed to act as an antagonist at fundus 5-HT 2B receptors. This lack of antagonist action was obvious when compared to the potent and competitive antagonism of 5-HT responses of these tissues in the presence of the non-selective 5-HT antagonist 1-NP.
  • Compound 1 produces physiological and behavioral responses indicative of 5-HTiA receptor activation at maximally effective erection enhancing doses using bioassays known to be indicative of 5-HT IA receptor activation such as the serotonin "behavioral syndrome" (Green & Backus, 1990). This syndrome includes hind limb abduction, flat body posturing, lower lip retraction and forepaw treading.
  • Rats were observed for the appearance of 1) flat body posture (lying flat on the ventral surface), 2) hindlimb abduction (hindlimbs fully extended behind the animal), 3) forepaw treading (clockwise circular motion of the forelimbs in a seated position) and 4) lower lip retraction (retraction of the lower lip such that incisors are visible).
  • Items 1-3 were scored according to their being absent (0), present (1), marked (2) or consistent (3).
  • Item 4 was scored according to incisor visibility as not visible (0), partially visible (1), half visible (2), fully visible (3), or gum and incisor fully visible (4).
  • 8-OHDPAT on the other hand significantly increased the appearance of all components of the behavioral syndrome at doses above 0.1 mg/kg (Table 13).
  • Systemic administration of 8-OHDPAT produced a marked and significant reduction of -1.5 ⁇ 0.1 ° C in core temperature of rats maintained at high ambient temperature ( Figure 17).
  • Compound 1 at a dose of 64 mg/kg increased temperature by +1.0 ⁇ 0.2 ° C, a significant effect compared to saline control rats which exhibited a slight reduction in core temperature of -0.06 ⁇ 0.2 ° C.
  • 4/5 of the Compound 1 treated animals exhibited convulsions and 1/5 of the animals died.
  • Table 13 shows the effects of increasing doses of Compound 1, m-
  • HLA Hindlimb abduction
  • FBP flat body posture
  • FPT forepaw treading
  • LLR lower lip retraction
  • 5-HT1 A receptors are known to exist as pre-synaptic somatodendritic receptors and post-synaptic receptors on serotonergic neurones and heteroreceptors on non-serotonergic nerve fibers (Fletcher et al., 1993, Trends Pharmacol. Sci. 41; Hoyer & Boddeke, 1993). Therefore activation of any one or a number of these receptors by non-selective drugs may be expected to produce a broad range of effects based on a summation of the different physiological responses that are activated or inhibited.
  • a full agonist would elicit a maximal hypothermic response but would also fail to prevent the hypothermia induced by 8-OHDPAT.
  • a partial agonist on the other hand would be expected to elicit a submaximal hypothermic response and also prevent the expression of maximal hypothermia produced by the full agonist 8- OHDPAT (Hoyer & Boddeke, 1993).
  • Increasing doses of Compound 1 produced a significant dose-related reduction in the hypothermic response to a standard dose of 8- OHDPAT.
  • the third set of experiments was performed to profile the dose- response relationship for hypo-and/or hyperthermia caused by Compound 1 and the interaction of the highest non-convulsive dose of Compound 1 with 8-OHDPAT.
  • Compound 1 at lower doses elicited a hypothermia compared to saline controls which did not appear to be dose-related.
  • the highest non-convulsive dose of Compound 1 did itself cause a hypothermia and attenuated the hypothermia induced by 8-OHDPAT this effect failed to reach the required level of significance.
  • the slight hypothermia induced by 2.0 and 8.0 mg/kg doses of Compound 1 also failed to reach significance compared to changes in core temperature in control animals.
  • a rat model of DOI induced head-twitch was used to determine the activity of Compound 1 at 5-HT2A receptors in vivo.
  • Arylpiperazines have previously been assessed for their ability to bind at 5-HT sites (Glennon et al., 1989; Anzini et al., 1995). Although a number of the arylpiperazines tested were shown to have reasonable affinity for the 5-HT sites, very little information is available regarding their effects in vivo using functional bioassays. In light of the fact that compounds examined in this study all produced bell-shaped dose-response curves for erection, and that some 5-HT 3 receptor antagonists have been reported to reduce erection, the aim of the present experiment was to compare and contrast the actions of Compound 1 with other arylpiperazines (e.g. m-CPP and TFMPP) in an in vivo assay of 5-HT 3 receptor activation, the von Bezhold-Jarisch reflex.
  • mice Male SD rats (350-500 g) were anesthetized with urethane (1.5 g/kg i.p.) and the right external jugular vein and the left common carotid artery were cannulated (PE 50 polypropylene tubing) for drug administration and blood pressure recording respectively. ECG was monitored and recorded from limb leads in a lead II configuration. The animals trachea was cannulated (14G Jelco intracath) to facilitate ventilation with room air (Ugo Basile respirator; 10 ml/kg; intrinsic rate).
  • Responses to control doses of 5-HT were determined 5 minutes after the administration of test compounds. Ten minutes after the last control dose of 5-HT atropine (600 ⁇ g/kg) was administered and the effects of the control dose of 5-HT were observed 5 minutes later.
  • 5-HT induced a dose-dependent bradycardia as an i.v bolus dose between 1-30 ⁇ g/kg.
  • doses above 100 ⁇ g/kg always produced A- V block such that 30 ⁇ g/kg was the maximum dose used in drug experiments.
  • Individual rats responded differently to 5-HT such that different doses were used in different animals to produce a similar bradycardia.
  • the median effective control dose for each group was between 1-30 ⁇ g/kg and produced bradycardia that was not significantly different between test groups.
  • 5-HT induced bradycardia and median effective doses were 108 ⁇ 10 (10 ⁇ g/kg), 101 ⁇ 13 (30 ⁇ g/kg), 124 ⁇ 6 (30 ⁇ g/kg), 109 ⁇ 6 (10 ⁇ g/kg) and 114 ⁇ 7 (10 ⁇ g/kg) beats per minute for Compound 1, quipazine, m-CPP, TFMPP and saline treated groups respectively (p > 0.50).
  • m-CPP 0.1-10 mg/kg
  • quipazine 0.00 l-.l mg/kg
  • the inhibition of 5-HT mediated bradycardia was complete (100%) for m-CPP whereas quipazine mediated inhibition of the response was approximately 50% at the highest dose tested.
  • These findings include: a) compounds of the invention elicited erection in rats in a manner dependent upon agonist action at post-synaptic 5-HT 2 c receptors within the CNS; b) compounds of the invention enhanced low grade erection and affiliative behaviors in non-human primates, c) compounds of the invention did not alter other central and peripheral pathways of erection; this was due to a lack of affinity for other serotonergic receptors and adrenergic receptors and d) compounds of the invention enhanced copulatory performance in normal and sexually exhausted male rats.
  • 5-HT 2A and 5-HT 2 c receptors exhibit close structural and pharmacological similarities such that it is difficult to envision a compound having the ability to act as an agonist at one of these receptors and an antagonist at the other. Therefore it is surprising to discover that compounds of the invention possess these properties. It is likely that compounds of the invention are uniquely able to adopt conformations which confer the correct combination of selective agonist, antagonist or neutral actions at specific receptors.

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Abstract

L'invention concerne des composés et des compositions contenant ces composés, qui sont efficaces pour le traitement ou la prévention des dysfonctions sexuelles (par exemple, en produisant une fonction favorisant l'érection) lorsque ces composés présentent une activité sélective de récepteur de la sérotonine (5HT). Dans un aspect, le composé est un agoniste de 5HT2c et un antagoniste de 5HT2a. Dans un autre aspect, le composé est un agoniste de 5HT2c, un antagoniste de 5HT2a et un agoniste de 5HT1a (faible).
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