EP0661972A1 - Utilisation de la spiperone ou de derives de la spiperone comme agents immunodepresseurs - Google Patents

Utilisation de la spiperone ou de derives de la spiperone comme agents immunodepresseurs

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Publication number
EP0661972A1
EP0661972A1 EP93902752A EP93902752A EP0661972A1 EP 0661972 A1 EP0661972 A1 EP 0661972A1 EP 93902752 A EP93902752 A EP 93902752A EP 93902752 A EP93902752 A EP 93902752A EP 0661972 A1 EP0661972 A1 EP 0661972A1
Authority
EP
European Patent Office
Prior art keywords
spiperone
alkyl
bromide
group
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP93902752A
Other languages
German (de)
English (en)
Other versions
EP0661972A4 (fr
Inventor
Richard J. Sharpe
Kenneth A. Arndt
Stephen J. Galli
Peter C. Meltzer
Raj K. Razdan
Howard P. Sard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beth Israel Deaconess Medical Center Inc
Original Assignee
Beth Israel Hospital Association
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
Priority claimed from US07/815,283 external-priority patent/US5290783A/en
Priority claimed from US07/831,429 external-priority patent/US5244902A/en
Priority claimed from US07/893,536 external-priority patent/US5703088A/en
Priority claimed from US07/893,534 external-priority patent/US5574041A/en
Application filed by Beth Israel Hospital Association filed Critical Beth Israel Hospital Association
Publication of EP0661972A4 publication Critical patent/EP0661972A4/fr
Publication of EP0661972A1 publication Critical patent/EP0661972A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • This invention is in the field of the suppression of immune responses, and in particular provides a method for the treatment of immune disorders that preferably includes administering an effective amount of spiperone or a spiperone derivative, or a pharmaceutically acceptable salt, including a quaternary salt, systemically or topically.
  • the immune system specifically recognizes and selectively eliminates foreign invaders, or other antigenic agents, by a process known as the immune response.
  • the immune response has three major characteristics: it responds adaptively to foreign invaders, it exhibits strong specificity, and it displays a long-term memory of earlier contacts with specific foreign pathogens or antigens.
  • the immune response involves the production of antibody and/or the destruction of antigenic cells by lymphocytes, which are highly specific for the antigen or hapten.
  • Cutaneous contact hypersensitivity responses are complex expressions of a cellular immune response characterized by antigen-dependent changes in lymphocyte traffic, the recruitment of circulating leukocytes to the site of antigen challenge (leukocyte infiltration) and alterations in vascular permeability and blood flow resulting in tissue swelling (edema) .
  • cutaneous contact hypersensitivity responses can occur on exposure to certain plant resins, such as those of poison ivy, and other commonly encountered agents in the environment. In individuals sensitized to such commonly encountered agents, a severe contact reaction can result upon exposure, with significant associated morbidity.
  • Severe or repeated contact hypersensitivity reactions can be followed by significant chronic changes, such as scarring of affected tissues, itchiness, swelling, scaling and oozing of tissue fluid through the skin surface. This pathology may predispose the patient to bacterial superinfection.
  • chronic immune responses can lead to diminished vision or actual blindness.
  • chronic immune responses such as chronic allergic asthma, can result in serious chronic lung disease.
  • Cutaneous contact hypersensitivity and asthma are just two examples of topical immune responses that can be associated with significant morbidity.
  • Others include atopic dermatitis, eczema, psoriasis, Sj ⁇ gren's Syndrome, including keratoconjunctivitis sicca secondary to Sj ⁇ gren's Syndrome, alopecia areata, allergic responses due to arthropod bite reactions, Crohn's disease, aphthous ulcer, ulcer, conjunctivitis, keratoconjunctivitis, ulcerative colitis, lichen planus, asthma, allergic asthma, cutaneous lupus erythematosus, dry eye associated with Sj ⁇ gren's Syndrome, scleroderma, vaginitis, proctitis, and drug eruptions.
  • immunologically mediated leukocyte infiltration (particularly infiltration of mononuclear cells, lymphocytes, neutrophils, and eosinophils) into the skin importantly contributes to the pathogenesis of these diseases.
  • Chronic eczema also is associated with significant hyperproliferation of the epidermis.
  • psoriasis a common cutaneous disease associated with a hyperproliferating epidermis, also has a leukocyte infiltration component.
  • I munologically mediated leukocyte infiltration also occurs at sites other than the skin, such as in the airways in asthma and in the tear producing gland of the eye in keratoconjunctivitis sicca. * * In addition to disorders that clearly represent
  • immune ⁇ ' responses are thought to contribute to many other pathological conditions, including Crohn's disease and ulcerative colitis of the gastrointestinal tract (inflammatory bowel disease) , psoriasis, alopecia 10 areata and others. While the cause of most of these disorders is unclear, it is thought that exogenous agents yet to be defined or components of the host's own tissues (in the case of autoimmune disorders) may provoke an immune response that is responsible for the 15 infiltration of lymphocytes, monocytes, and granulocytes observed in these conditions. It is also believed that the infiltrating cells significantly contribute to the tissue pathology associated with these disorders, through the production of cytokines 20 as well as other mechanisms.
  • corticosteroids when administered systemically, are effective in this regard but are associated with significant and potentially dangerous side effects. Topically applied corticosteroids have some efficacy in treating these conditions, but are only partially effective in many instances and have their own significant side effects, including atrophy of tissue, formation of telangiectasia, blanching, and a myriad of systemic effects if significantly absorbed.
  • agents with partial utility for treating some of the above conditions include psoralen plus ultraviolet A (PUVA) , cyclosporin A, or azathioprine, but the risk-to- benefit ratios for these agents is unfavorable for most of the conditions described above.
  • PUVA psoralen plus ultraviolet A
  • cyclosporin A cyclosporin A
  • azathioprine psoralen plus ultraviolet A
  • pathogenic or undesired systemic immune responses include host rejection of foreign organ or tissue transplants; graft-vs-host disease in which donor immunological cells present in the graft attack host tissues in the recipient of the graft; diseases with proven or possible autoimmune components, such as rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, psoriasis, leprosy reversal reactions, erythema nodosum leprosum, autoimmune uveitis, multiple sclerosis, allergic encephalomyelitis, systemic lupus erythematosis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearing loss, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, polychondritis, scleroderma, Wegener's granulomatosis, chronic active hepatitis, myasthenia gravis,
  • systemic immunosuppressants include steroid hormones, anti-metabolites such as methotrexate and azathioprine, cyclosporine, alkylating agents such as cyclophospha.ttide and busulfan, and certain antibiotics.
  • anti-metabolites such as methotrexate and azathioprine
  • cyclosporine cyclosporine
  • alkylating agents such as cyclophospha.ttide and busulfan
  • certain antibiotics include steroid hormones, anti-metabolites such as methotrexate and azathioprine, cyclosporine, alkylating agents such as cyclophospha.ttide and busulfan, and certain antibiotics.
  • an inflammatory response is a pathologic condition that can occur in response to immunologically non-specific injury, either from physical (such as trauma) , chemical, or biologic agents.
  • An inflammatory response is characterized by increased blood flow and redness in the inflamed area, increased capillary permeability and edema, and recruitment of immunologically non-specific white blood cells, especially neutrophils, that remove injurious material and promote repair.
  • inflammatory responses do not respond adaptively to the inciting stimulus, do not show specificity and do not exhibit long term memory.
  • Phenylbutazone, indomethacin, aspirin, ibruprofen, and acetaminophen are examples of antiinflammatory compounds which have no significant immunosuppressive activity, as demonstrated by their lack of a significant effect on immunological mediated responses, such as contact hypersensitivity.
  • Spiperone (8-[3- ⁇ p-fluorobenzoyl ⁇ propyl]-l- propyl]-1-phenyl-l,3,8-triazaspiro-[ .5]decan—-one) is a neuroleptic agent with central nervous system (CNS) dopamine and serotonin (5-HT) receptor antagonist properties. Some analogues of spiperone are useful as experimental reagents in dopamine and serotonin receptor studies.
  • CNS central nervous system
  • U.S. Patent No. 3,996,363 to Wade and U.S. Patent No. 4,839,342 to Ooms, et al. disclose methods to promote wound healing that include the application of spiperone or a derivative thereof.
  • Wound healing is a reparative process by which several types of resident cells, such as epithelial cells, fibroblasts and vascular endothelial cells, and certain circulating cells, including neutrophils, lymphocytes 5 and macrophages, act in concert to restore to a more f healthy condition tissues that have sustains? " various* forms of mechanical or other injury.
  • lymphT.ytes and macrophages participate in both wound heal and in immune responses, the specific roles of 10 thest alls in the two types of processes may be distinct.
  • the parent spiperone has a strong neuroleptic effect when administered systemically, but not when administered topically. It is used in the examples as a model of an active immunosuppressant.
  • a spiperone derivative, or its pharmaceutically acceptable salt, or a salt of the parent spiperone that does not have a significant neuroleptic effect is administered.
  • Spiperone or its derivative or pharmaceutically acceptable salt is a preferred immunosuppressant if it suppresses the leukocyte infiltrate and/or the ear swelling associated with an experimental contact hypersensitivity response by at least 40% at 24 hours after specific antigen challenge.
  • the active compound is administered, for example, by injection, in a pharmaceutical carrier such as saline, in an amount effective to immunosuppress the patient.
  • a pharmaceutical carrier such as saline
  • the derivatives are administered topically in a suitable carrier to effectively immunosuppress the patient at the site of application, without producing a significant neuroleptic effect.
  • Other pharmaceutical compositions include a spiperone derivative combined with a cycloamylose, such as cyclodextrin, which can be used to modify the pharmokinetics of the compound.
  • Spiperone and its active derivatives are useful as topical agents in treating contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sj ⁇ gren's Syndrome, including keratoconjunctivitis sicca secondary to Sj ⁇ gren's Syndrome, alopecia areata, allergic responses due to arthropod bite reactions, Crohn's disease (inflammatory bowel disease) , aphthous ulcer, ulcer, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions.
  • the novel method may also be useful in reducing the infiltration of skin by malignant leukocytes in diseases such as mycosis f igoides.
  • These compounds can also be used to treat an aqueous-deficient dry eye state (such as immune mediated keratoconjunctivitis) in a patient suffering therefrom, by administering the compound topically to the eye.
  • Figure 1 Effect of systemic spiperone (30 or 150 mg/kg, subcutaneously) on the tissue swelling associated with oxazolone-induced cutaneous contact hypers ⁇ itivity reactions.
  • the change in ear thickness (post-challenge value minus baseline pre-challenge value) was measured 24 hours after oxazolone challenge. Ti.**. data are presented as the mean ⁇ SEM (standard error of the mean) .
  • Figure 2 Effect of systemic treatment with 30 or 150 mg/kg spiperone, subcutaneously, on le ⁇ rocyte infiltration associated with 24-hour contact hypersensitivity reactions.
  • -.a mean ⁇ SEM
  • T iction in leukocyte infiltration observed ... lals treated with 30 or 150 mg/kg spiperone r ⁇ -- nificant when compared to the reactions observed in animals t-eated with vehicle alone (* or ** p ⁇ 0.05 or 0.01, respectively) .
  • Figure 3 Comparative effects of systemic vehicle (1), haloperidol (2), trazadone (3), mianserin (4) or spiperone (5) (all agents at 40 mg/kg, subcutaneously) on the tissue swelling associated with oxazolone-induced cutaneous contact hypersensitivity reactions.
  • Spiperone, the other agents, or vehicle alone were administered to BALB/c mice 1 hour after challenge for contact hypersensitivity.
  • the change in ear thickness (post-challenge value minus baseline pre-challenge value) was measured 24 hours after oxazolone challenge. The data are presented as the mean ⁇ SEM.
  • Figure 4 Comparative effect of systemic treatment with vehicle (1) or haloperidol (2) , trazadone (3) , mianserin (4) or spiperone (5) (all agents at 40 mg/kg) , administered subcutaneously, on leukocyte infiltration associated with 24-hour contact hypersensitivity reactions.
  • vehicle (1) or haloperidol (2) , trazadone (3) , mianserin (4) or spiperone (5) all agents at 40 mg/kg
  • FIG. 5 Effect of spiperone applied topically during the period of sensitization on the tissue swelling associated with oxazolone-induced contact hypersensitivity reactions.
  • Oxazolone was applied to the abdomens of BALB/c mice on day 0. The change in ear thickness was determined 24 hours after challenge with oxazolone on day 6.
  • Figure 6 Effect of spiperone applied topically during the period of sensitization on the leukocyte infiltration associated with oxazolone-induced contact hypersensitivity reactions. These data (mean ⁇ SEM) are from the same mice whose ear thickness measurements are presented in Figure 5i Topical treatment with spiperone significantly diminished the reactions when compared to those in vehicle-treated mice (**p ⁇ 0.01) .
  • Figure 7a,b,c Effect of topically administered spiperone on tissue swelling associated with oxazolone-induced contact hypersensitivity reactions.
  • Oxazolone was applied to both ears of all mice and the change in ear thickness was measured at a specified interval thereafter.
  • a One hour after oxazolone challenge, 4.0% spiperone in ethanol:propylene glycol:olive oil was applied to both surfaces of the right ears of some mice, whereas vehicle alone was applied to both surfaces of the right ears of the control (0% spiperone) mice. The ears were measured 24 hours after oxazolone challenge.
  • FIG. 9 Effect of topically administered spiperone on tissue swelling associated with DNFB- induced contact hypersensitivity reactions.
  • DNFB was applied to both ears of C57BL/6J mice.
  • 0.5% spiperone was applied to both surfaces of the right ears of some mice, whereas vehicle alone was applied to both surfaces of the right ears of the control (0% spiperone) mice.
  • the change in ear thickness was determined 24 hours after challenge with DNFB.
  • Treatment with spiperone significantly diminished contact hypersensitivity reactions in the right ears of the treated animals (**p ⁇ 0.01 when compared to the right ears in the control mice, and p ⁇ 0.05 when compared to the contralateral ears of the same mice) .
  • FIG 11 Comparative effects of varying doses of systematically administered spiperone methyl quaternary ammonium bromide salt versus spiperone on tissue swelling associated with oxazalone-induced cutaneous contact hypersensitivity reactions.
  • Spiperone or spiperone methyl quaternary ammonium bromide salt were administered to Balb/c mice 1 hour after challenge for contact hypersensitivity.
  • the change in ear thickness (post-challenge value minus baseline pre-challenge value) was measured 24 hours after oxazalone challenge.
  • the data is presented as the mean ⁇ SEM.
  • Figure 12 Comparative effects of systemic treatment (intraperitoneal) with vehicle (0 mg/kg) or varying doses of spiperone or spiperone methyl quaternary ammonium bromide salt on leukocyte infiltration associated with 24-hour contact hypersensitivity reactions.
  • the data (mean ⁇ SEM) are derived from the same mice whose ear thickness values are shown in Figure 11.
  • Doses of 30 mg/kg, 15 mg/kg and 6 mg/kg of spiperone methyl quaternary ammonium bromide salt resulted in significant suppression of leukocyte infiltration.
  • alkyl refers to a saturated straight, branched, or cyclic hydrocarbon * of C, to Cj-, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2- dimethylbutyl, and 2,3-dimethylbutyl.
  • aryl refers to phenyl or substituted phenyl, wherein the substituent is independently halo, alkyl, or oxy(alkyl) (for example, methyoxy, et " xy, etc.), and wherein the aryl can have up to three substituents.
  • the parent spiperone is 8-[3-(p- fluorobenzoyl)propyl]-l-phenyl-l,3,8- triazaspiro[4.5]decan-4-one, which has the structure illustrated below.
  • Example 1 shows that spiperone can be given topically to produce local immunosuppression without inducing a significant neuroleptic effec ...
  • j H; alkyl, specifically including CH 3 -, cyclohexyl, (CH 3 ) 2 CH-, CH 3 (CH 2 ) 3 -, (CH 3 ) 2 CHCH 2 -, CH 3 CH 2 CH(CH 3 )-, (CH 3 ) 3 C-, and -CH 3 (CH 2 )p; Y-CH 2 (CH 2 ) n - or Ar, specifically including C 6 H 5 -, (2, 3, or 4)-(OCH 3 )C 6 H 4 - and (2, 3, or 4)-(CH 3 )C ⁇ H 4 -; 2-X-C 6 H 4 -, 3-X-C 6 H 4 -, or 4-X-C 6 H 4 -;
  • R 2 H or C j to C- 20 alkyl
  • R 3 H; alkyl, specifically including -CH 3 , CH 3 CH 2 — , CH 3 CH 2 CH 2 — , (CH 3 ) 2 CH— , or CH (CH 2 ) n — ; CN(CH 2 ) 2 -; X-(CH 2 )n-; X-(CH 2 ) n C0-; NH 2 C(NH)NHC(NH) (aryl) (CH 2 ) n -; or X-(aryl) -(CH 2 ) n-;
  • R 4 H, C 6 H 5 CH(CH 2 CH 3 )CH 2 -, C 6 H 5 CH(CH 3 ) (CH 2 ) 2 -, CgH 5 CH 2 CH ( CH ) CH 2 *— , C 6 H 5 CH 2 CH 2 CH ( CH 3 ) — , C 6 H 5 CH(CH 3 ) (CH 2 ) 3 -,
  • Y-CH 2 (CH 2 ) n -, Ar,-(CH 2 ) n -, C, to C 20 alkyl, X-(CH 2 ) n CO-, or X-(CH 2 ) n -; n 1 to 6; p is 1 to 20;
  • X is independently F, Cl, Br, I, OCH 3 , S0 3 " , NH 2/ H, -OH, -COOH, -COOR, -S0 3 H, -CN, -NHS0 3 H, -N0 2 , or -S0 2 NH 2 ;
  • Arj is, independently, aryl, (2, 3, or 4-X-C 6 H 4 -) , (2, 3, or 4)-(CH 2 X)C 6 H 4 -, (2, 3, or 4) -(CX 3 ) C 6 H 4 -, (2, 3, or 4)-(CHX 2 )C 6 H 4 -, 2-thienyl, or (2, 3, or 4)-X- C 6 H 4 CH 2 -; or its pharmaceutically acceptable salt, including any quaternary salt known by those in the art, and specifically including the quaternary ammonium salt of the formula -NR + Z " , wherein R is alkyl (and in particular methyl or ethyl) or benzyl, and Z is a counteranion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, sulfate, phosphate, or carboxylate (
  • spiperone forms that are particularly useful for systemic delivery are those in which R t through R t are chosen to minimize neuroleptic activity and to maximize immunosuppressant activity of the molecule, or wherein spiperone or the spiperone derivative is in the form of a quaternary salt.
  • spiperone to act as-an immunosuppressant
  • the potential utility of any one of the above- described forms of spiperone to act as-an immunosuppressant can be conveniently determined by synthesizing the compound and testing it in the biological assay described in Example 1.
  • the neuroleptic activity of the spiperone derivative or salt can be evaluated as described in Example 3.
  • the efficacy of spiperone derivatives can also be assessed using animal models of allograft rejection, experimental allergic encephalomyelitis, lupus erythematosus, Freund's adjuvant arthritis and/or graft versus host disease.
  • Measurement of their ability to bind to serotonin or dopamine receptors can be carried out as described in detail in Example 3, or by their lack of ability to act as a tranquilizer or neuroleptic in mammals, for example, by demonstrating that they are no different than placebo in the hot plate test of Eddy, et al. , J. Pharmacol. 107:385 (1953) and 110:135 (1954).
  • immunosuppressive compounds with a spiperone nucleus that have a neuroleptic effect can be complexed or modified to eliminate that effect for systemic delivery, by one or more of the following processes.
  • Compounds with a spiperone nucleus that exhibit an immunosuppressive effect yet also exhibit a neuroleptic effect can be modified to minimize the neuroleptic effect by decreasing the lipophilicity (equivalent to increasing the hydrophilicity) of the molecule. This can be done by adding one or more charged side chain(s) onto the molecule or by altering the existing side chain to make it more polar. The hydrophilicity of spiperone derivatives will in general increase when charged substituents are added.
  • Another technique for reducing the Size of the Molecule is to increase the size of the molecule via a covalent linkage to a large moiety (e.g. , albumin or polyethylene glycol) , using standard techniques of organic synthesis or by choosing a spiperone derivative with large substitutions (R,, R 2 , R 3 , or R,) .
  • a large moiety e.g. , albumin or polyethylene glycol
  • a fourth method for reducing the central nervous system (CNS) effects of a compound that contains a spiperone nucleus includes forming a non-covalent complex of the compound with a cyclic molecule such as a cycloamylose (e.g., a cyclodextrin such as ⁇ -cyclodextrin) , which has a spatial arrangement of hydroxyl groups whereby the outer surface of the ring formed by the cycloamylose is hydrophilic and the inner surface is lipophilic.
  • a cyclic molecule such as a cycloamylose (e.g., a cyclodextrin such as ⁇ -cyclodextrin)
  • this structure When utilized in aqueous solution, this structure permits molecules (or parts thereof), termed “guest molecules”, which are less polar than water and which are of suitable dimensions, to be incorporated into the lipophilic inner cavity, such that the cycloamylose/guest molecule complex presents to the blood-brain barrier as a relatively large and polar compound which is unable to penetrate the barrier.
  • guest molecules molecules (or parts thereof), termed “guest molecules”, which are less polar than water and which are of suitable dimensions, to be incorporated into the lipophilic inner cavity, such that the cycloamylose/guest molecule complex presents to the blood-brain barrier as a relatively large and polar compound which is unable to penetrate the barrier.
  • Such complexes may be prepared by any method known to the art, including those described in U.S. Patent No. 4,555,504, which discloses ⁇ -cyclodextrin complexed with digoxin.
  • Spiperone altered or complexed by any of the above methods is referred to herein as "a spiperone derivative without significant neuroleptic effect.”
  • the efficacy of any such spiperone entity as an immunosuppressant can be tested in the assay described in Example 1 below. Whether the same entity is capable of inducing the neuropharmacological side effects observed for spiperone can be assayed by, for example, the hot plate test of Eddy et al., J ⁇ . Pharmacol. 107:385 (1953) and 110:135 (1954), or by the method of Example 3.
  • the central nervous system side effects of a spiperone derivative can be estimated using molecular modeling and/or pharmacophore analysis.
  • the dopamine and serotonin receptors are well characterized and strategies for estimating binding of drugs to these receptors are well established.
  • Schmidt, et al., Molecular Pharmacology 38:511-516 (1990) describe an algorithm for e s timating the binding affinity of drugs to the
  • Spiperone or its above-defined derivative can be administered in the form of a pharmaceutically acceptable quaternary salt.
  • Quaternary salts are typically less lipophilic than the corresponding unquaternized compound, and therefore have a decreased effect on the central nervous system.
  • Nonlimiting examples of quaternary salts that can be used include, but are not limited to salts prepared from methyl chloride, methyl bromide, methyl iodide, methyl sulfate, ethyl sulfate, methyl benzene-sulfonate, methyl p-toluenesulfonate, ethyl p-toluenesulfonate, ethyl chloride, ethyl bromide, ethyl iodide, n-propyl chloride, n-propyl bromide, n-butyl bromide, isobutyl bromide, sec-butyl bromide,
  • spiperone or its derivative can be administered as a quaternary salt of the formula -NR + Z " , wherein R is alkyl (and in particular methyl or ethyl) or benzyl, and Z is a counteranion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, sulfate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, propionate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate) .
  • R is alkyl (and in particular methyl or ethyl) or benzyl
  • Z is a counteranion, including chloride, bromide, iodide, -O-alkyl, to
  • Mammals, and specifically humans, suffering from pathogenic immune responses can be treated by topical or ' systemic administration to the patient of an effective amount of spiperone or its derivative or pharmaceutically acceptable salt, optionally in the presence of a pharmaceutically acceptable carrier or diluent.
  • the spiperone derivative is administered subcutaneously, intravenously, intraperitoneally, intramuscularly, parenterally, orally, submucosally, - by inhalation, transdermally via a slow release patch,
  • Typical systemic dosages for all • of the herein described conditions are those ranging from 0.1 mg/kg to 50*. mg/kg of body weight per day as a single daily dose or divided daily doses.
  • Typical 10 dosages for topical application are those ranging from 0.001 to 100% by weight of the active compound.
  • local immunosuppression can be achieved by administering topically lower doses of spiperone derivatives than would be required if t--e agents were 15 administered systemically.
  • the effective dosage of the parent compound, spiperone, for systemic immunosuppression is believed to be higher than the effective dosage of spiperone for inducing a neuroleptic effect.
  • the spiperone derivative is administered for a sufficient time period to alleviate the undesired symptoms and the clinical signs associated with the condition being treated.
  • the active compound is included in the 25 pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutic amount of compound of the spiperone derivative in vivo in the absence of serious toxic effects.
  • concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill ⁇ ' n the art. It is to be noted that dosage values will also vary with the 35 severity of the condition to be alleviated.
  • compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
  • dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.
  • the spiperone derivative or its salts can be any suitable spiperone derivative or its salts.
  • a syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the spiperone derivative can also be mixed with 10 other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, antiinflam atories, antivirals, or other immunosuppressive agents.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene 20 glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as 25 acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oils
  • pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, 30 disposable syringes or multiple dose vials made of glass or plastic.
  • preferred carriers are physiological saline,bacteriostatic ⁇ water, Cremophor ELTM (BASF, Parsippany, NJ) or
  • PBS 35 phosphate buffered saline
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions are also preferred as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (which is incorporated herein by reference in its entirety) .
  • liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container.
  • aqueous solution of the spiperone derivative is then introduced into the container.
  • the container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
  • Suitable vehicles or carriers for topical application can be prepared by conventional techniques, such as lotions, suspensions, ointments, creams, gels, tinctures, sprays, powders, pastes, slow-release transdermal patches, suppositories for application to rectal, vaginal, nasal or oral mucosa.
  • thickening agents, emollients, and stabilizers can be used to prepare topical compositions.
  • thickening agents examples include petrolatum, beeswax, xanthan gum, or polyethylene, humectants such as sorbitol, emollients such as mineral oil, lanolin and its derivatives, or squalene.
  • humectants such as sorbitol
  • emollients such as mineral oil, lanolin and its derivatives, or squalene.
  • Spiperone derivatives can be provided in the form of pharmaceutically-acceptable salts.
  • pharmaceutically-acceptable salts or complexes refers to salts or complexes that retain the desired bic .gical activity of the parent compound and exhibit minimal, if any, undesired toxicological effects.
  • salts examples include (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like) , and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acids, naphthalenedisulfonic acids, and polygalacturonic acid; (b) base addition salts formed with polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, and the like, or with an organic cation formed from N,N-dibenzylethylene-diamine or ethylenediamine; or (c) combinations of (a) and (b) ; e.g., a
  • Spiperone derivatives are capable of acting systemically or topically to suppress the immune response in animals.
  • the compounds, or therapeutic compositions thereof are useful for the • treatment of a myriad of immunological disorders.
  • disorders that are usually treated systemically include those related to host rejection of foreign organ or tissue transplants; graft-vs-host disease; and autoimmune diseases, such as rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, psoriasis, autoimmune uveitis, multiple sclerosis, allergic encephalomyelitis, systemic lupus erythematosis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearing loss, aplastic anemia, pure red cell anemia, idiopathic thrombocytopeni , polychondritis, scleroderma, Wegener's granulomatosis, chronic active hepatitis, myasthenia grav
  • Graves ophthalmopathy sarcoidosis, primary biliary cirrhosis, primary juvenile diabetes, uveitis posterior, and interstitial lung fibrosis; and allergic reactions, including atopic dermatitis and contact dermatitis.
  • Examples of other immune disorders of the skin, mucosa, or eye that generally are treated topically (although many can also be treated systemically) include alopecia areata, arthropod bites, lichen planus, cutaneous lupus erythematosus, scleroderma, dry eye associated with Sj ⁇ gren's syndrome, and drug reactions.
  • the compounds are specifically useful in the treatment of allograft rejection, for example, of heart, kidney, and lung tissue, and in the treatment of graft vs. host disease associated with bone marrow transplants.
  • the ability of the neuroleptic agent spiperone (8-[3- ⁇ p-fluorobenzoyl ⁇ propyl]-l-phenyl-1,3,8- triazaspiro-[4.5]decan-4-one) to influence the tissue swelling and leukocyte infiltration associated with contact hypersensitivity reactions in mice was evaluated as described in detail in Example 1.
  • the parent spiperone compound was used for the procedure in Example 1 as a model of an active immunosuppressant.
  • Other compounds with a spipe- nucleus can be measured against this el, and - ⁇ ⁇ republic
  • Example 1 contact hypersensitivity reactions were elicited by applying the haptens oxazolone or dinitrofluorobenzene topic lly to one or both ears five to eight days after epicu-.aneous sensitization.
  • spiperone was given subcutaneously at a dose of 150 mg/kg, 1 hour after challenge with oxazolone, cutaneous contact hypersensitivity to this hapten was almost totally abrogated.
  • a dose of 40 or 30 mg/kg subcutaneously also significantly suppressed the reactions but to a lesser degree than the higher dose.
  • spiperone When applied topically, preparations of spiperone significantly suppressed both the tissue swelling and the leukocyte infiltration associated with the elicitation phase of contact hypersensitivity to either oxazolone or dinitrofluorobenzene. Topical treatment with spiperone also suppressed the sensitization phase of contact sensitivity. However, mice treated topically with spiperone, unlike those treated systemically, exhibited no drowsiness or other evidence of central nervous system effects. Spiperone expresses both serotonin and dopamine receptor antagonist activity.
  • spiperone unlike spiperone, it was discovered that the chemically unrelated serotonin antagonists, trazadone and mianserin, and the dopamine receptor antagonist, haloperidol, were not effective in suppressing contact hypersensitivity. Additionally, the methyl quaternary ammonium bromide salt of spiperone has substantially reduced CNS activity, while retaining immunosuppressive activity. On the basis of this, it is clear that the mechanism of action of spiperone on the immune response is independent of its serotonin or dopamine receptor blocking properties, and therefore, spiperone derivatives with immunosuppressive effect yet without neuroleptic effect can be provided by the method of selection disclosed generally herein.
  • Example 1 Inhibition of Induced Contact Hypersensitivity.
  • mice Six-to-8-week-old female C57BL/6J or BALB/c mice were obtained from the Jackson Laboratory, Bar Harbor, Maine or from Charles River Laboratories, Kingston Facility, Stoneridge, NY, respectively. Spiperone, mianserin, trazadone, haloperidol and oxazolone were purchased from the Sigma Chemical Co. (St. Louis, MO) .
  • Oxazolone-induced Contact Hypersensitivity - Sensitization and challenge for contact hypersensitivity were performed as follows. The abdomens of the mice were shaved with electric clippers, 50 ⁇ l of a 4% (w/w) solution of oxazolone in 4:1 (v:v) acetone:olive oil were applied to the shaved abdomen, and 5 ⁇ l of the same solution were applied to each hind footpad.
  • mice Five to eight days later, the mice were challenged for contact hypersensitivity by applying 10 ⁇ l of a 0.5% (w:w) solution of oxazolone in 4:1 (v:v) acetone:olive oil to both the inner and outer surface of the right ear of each mouse (in the case of mice treated systemically with spiperone) or to both ears (in the case of mice treated topically with spiperone) .
  • Dinitrofluorobenzene-Induced Contact Hyr -sensitivity - Mice were treated in an identical ma; tr as above, except that 0.2% (v:v) 1-fluoro-2,4- a dinitrobenzene (DNFB) in acetone was used for both
  • mice were treated 10 subcutaneously with spiperone (150 or 30 mg/kg body weight) in 0.1 ml of carrier (Cremophor EL, BASF, Parsippany, NJ) , or with 0.1 ml of carrier alone.
  • spiperone 150 or 30 mg/kg body weight
  • carrier Carrier
  • mice were treated in a similar fashion with 40 mg/kg body weight of trazadone, 15 mianserin, haloperidol, or spiperone in 0.1 ml olive oil or with olive oil alone.
  • Topical Spiperone Treatment To test whether spiperone affected the sensitization phase of contact hypersensitivity, 50 ⁇ l of 0.08% spiperone in 20 propylene glycol was applied to the shaved abdomens of the mice on days -2, -1, 0, 1 and 2, with the day of oxazalone sensitization being designated day 0.
  • mice To test the effects of spiperone on the expression of contact hypersensitivity in mice already sensitized to 25 oxazolone; mice were treated with spiperone topically at two hours before or one or twenty-two hours after challenge for contact hypersensitivity, by applying 10 ⁇ l of a solution of spiperone in vehicle to both sides of the right ear.
  • the increment (delta) in ear thickness (ear swelling) was calculated as the 24- or 46-hour value minus the baseline (pre-challenge) value and expressed in units of 10" 2 mm. Mice were killed by cervical dislocation after the measurement of 24-hour ear thickness was obtained, and the ears were processed for histologic examination.
  • mice we_e treated with spiperone at 30 mg/kg subcutaneously (Figs. 1 and 2) .
  • spipc 5ne diminished the tissue swelling associated with contact hypersensitivity to oxazolone to almost the same extent as did the higher dose (68% reduction with 30 mg/kg versus 80% reduction with 150 mg/kg) but reduc&d the leukocyte infiltration associated with the reaction by only 37% (Fig. 2) .
  • the central nervous system effects of spiperone at 30 mg/kg were substantially less pronounced that those observed at the higher dose.
  • the mice treated with spiperone at 30 mg/kg were less sleepy than those treated with 150 mg/kg.
  • the mice treated with 30 mg/kg appeared somewhat lethargic and were less interested in food and water than were control mice treated with carrier alone.
  • systemic spiperone Versus Other Serotonin or Dopamine Receptor Antagonists -
  • systemic spiperone was compared to the serotonin receptor antagonists, trazadone or mianserin, and to the dopamine receptor antagonist, haloperidol, for their ability to inhibit cutaneous contact hypersensitivity.
  • a dose of 40 mg/kg only systemic spiperone significantly reduced cutaneous contact hypersensitivity (Fig. 3, 4).
  • the degree of lethargy in mice treated with 40 mg/kg of spiperone, trazadone, mianserin or haloperidol systemically appeared to be about the same as that in the mice treated with 30 mg/kg of spiperone systemically.
  • mice were treated topically with spiperone in Vehicle-N or Vehicle-N alone, applied to the abdomen beginning two days prior to sensitization and continuing for a total of 5 days (Figs. 5 and 6) .
  • Mice treated with spiperone exhibited 64% less tissue swelling and 70% less leukocyte infiltration at sites of hapten challenge than did vehicle-treated mice (p ⁇ 0.0l for either comparison) .
  • mice were similarly treated, but with vehicle alone topical administration of a 4.0% suspension of spiper .,e in absolute ethanol, propylene glycol, and olive oil one hour after hapten challenge resulted in a marked diminution of the tissue swelling associated with contact hypersensitivity reactions elicited in the right (spiperone-treated) ear and had a smaller, but nonetheless significant, effect on the swelling associated with the contact hypersensitivity reaction elicited on the contralateral (untreated) ear (Fig. 7a) .
  • reactions in the untreated right ears v. ⁇ .
  • Topical treatment with spiperone significantly diminished the tissue swelling associated with reactions to DNFB (by 45%, Fig. 9) and had an even more significant effect on leukocyte infiltration (a reduction of 71% compared to right ears of vehicle-treated mice, Fig. 10) .
  • Example 2 Comparison of Immunosuppressant versus Anti-inflammatory activity.
  • Example 3 Evaluation of Serotonin Receptor Binding Activity or Dopamine Receptor Binding Activity of Spiperone Derivatives.
  • Spiperone derivatives which lack serotonin 30 receptor binding or dopamine receptor binding activity can be identified as follows.
  • a radiolabeled ligand known to bind serotonin and/or dopamine receptors can be bound to an appropriate substrate expressing one or both of these receptors.
  • radiolabeled -.35 quipazine which is available commercially can be used as the ligand.
  • the spiperone derivative to be tested is then incubated with the radiolabeled quipazine ligand combination.
  • Displacement of radiolabeled ligand is positive evidence that the spiperone derivative being tested can bind serotonin and/or dopamine receptors.
  • the amount of radiolabeled ligand which is displaced is determined by an appropriate standard curve which can also provide information concerning binding affinities.
  • the displaced radiolabeled ligand can be quantitated using a standard scintillation counter.
  • rat cortices are homogenized in 20 volumes of 50 mM Tris HCl buffer pH 7.7 at 25°C and centrifuged at 49,000 x g for 10 min. The pellet is resuspended in fresh buffer and incubated at 37°C for 10 min.
  • the pellet is resuspended in 80 volumes of Krebs-HEPES buffer (25 mM HEPES, 118 mM NaCl, 5 mM KCl, 2.5 mM CaCl 2 , and 1.2 mM MgCl 2 pH adjusted to 7.4) .
  • Tissue (10 mg of original wet weight) is added'to assay tubes containing 0.8 nM [ 3 H] uipazine and displacing drug or buffer in a final volume of 1 ml.
  • Non-specific binding is defined using 1 micro ole zacopride. After a 30 min incubation at room temperature, the tissue is rapidly filtered under vacuum through No.
  • Spiperone derivatives which have binding affinities for dopamine and/or serotonin receptors of one/tenth or less than native spiperone are considered to be potentially useful as systemic im unosuppressants if they are at least 50% as active as native spiperone on a weight basis in suppressing immunologically specific responses such as contact hypersensitivity.
  • Example 4 Immunosuppressive and CNS Effect of the Methyl Quaternary Ammonium Salt of Spiperone
  • the methyl quaternary ammonium bromide salt of spiperone was prepared by the following procedure. Spiperone (Sigma, 4.0 gm, 10 mmol) was dissolved in a 1:1 mixture of warm methylene chloride and methanol (80 mL) . The solution was transferred to a Wheaton pressure bottle. Methyl bromide (2N in ether, 8 mL,
  • Figures 11 and 12 illustrate the effect of spiperone and the methyl quaternary ammonium bromide salt of spiperone when injected intraperitoneally at different dosages on oxazolone induced contact hypersensitivity.
  • the mice were injected with the test compound one hour after oxazolone challenge, and ear thickness measured at 24 hours after challenge.
  • the dosages used are indicated in Table 1.
  • the CNS effects were assessed by periodically observing the activity of the animals over a 23 hour period following injection of the test substance. The following scoring* system was used and corresponded to the maximal effect observed during any observation period. 4+ Comatose
  • the methyl quaternary ammonium bromide salt of spiperone significantly reduced ear swelling as compared to the control at dosages as low as 1.5 mg/kg, and had no appreciable CNS effect at dosages up to 6 mg/kg.

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Abstract

Méthode de dépression de la réponse immunitaire chez les mammifères consistant à traiter le mammifère de façon locale ou parfois générale avec une dose efficace de spiperone ou de dérivé de la spiperone, ou avec son sel pharmaceutiquement acceptable, y compris sel quaternaire.
EP93902752A 1991-12-27 1992-12-23 Utilisation de la spiperone ou de derives de la spiperone comme agents immunodepresseurs Withdrawn EP0661972A1 (fr)

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US831429 1986-02-20
US815283 1991-12-27
US07/815,283 US5290783A (en) 1990-03-16 1991-12-27 Use of spiperone derivatives as immunosuppressant agents
US07/831,429 US5244902A (en) 1989-08-21 1992-02-05 Topical application of spiperone or derivatives thereof for treatment of pathological conditions associated with immune responses
US893534 1992-06-04
US07/893,536 US5703088A (en) 1989-08-21 1992-06-04 Topical application of spiperone or derivatives thereof for treatment of pathological conditions associated with immune responses
US07/893,534 US5574041A (en) 1990-03-16 1992-06-04 Use of spiperone derivatives as immunosuppressant agents
PCT/US1992/011205 WO1993012789A1 (fr) 1991-12-27 1992-12-23 Utilisation de la spiperone ou de derives de la spiperone comme agents immunodepresseurs
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US5703088A (en) * 1989-08-21 1997-12-30 Beth Israel Deaconess Medical Center, Inc. Topical application of spiperone or derivatives thereof for treatment of pathological conditions associated with immune responses
US5693645A (en) * 1992-12-23 1997-12-02 Beth Israel Deaconess Medical Center, Inc. Use of spiperone or spiperone derivatives as immunosuppressant agents
US5484788A (en) * 1993-03-26 1996-01-16 Beth Israel Hospital Association Buspirone as a systemic immunosuppressant
US5631017A (en) * 1993-03-26 1997-05-20 Beth Israel Deaconess Medical Center, Inc. Topical application of buspirone for treatment of pathological conditions associated with immune responses
US5637314A (en) * 1995-06-07 1997-06-10 Beth Israel Deaconess Medical Center, Inc. Topical and systemic application of buspirone or derivatives thereof for treating atopic dermatitis
WO1997023221A1 (fr) * 1995-12-21 1997-07-03 Eli Lilly And Company Methode de traitement de dermatites
EP1080091A1 (fr) * 1998-05-18 2001-03-07 Novo Nordisk A/S Nouvelles 1,3,8-triazaspiro[4.5]decanones possedant une affinite elevee pour les sous-types du recepteur opioide
US6277991B1 (en) 1998-05-18 2001-08-21 Novo Nordisk A/S 1,3,8-triazaspiro[4.5]decanones with high affinity for opioid receptor subtypes
US20050191302A1 (en) * 2002-08-29 2005-09-01 University Of Southampton Treatment for liver disease
NZ538307A (en) 2002-09-09 2008-04-30 Janssen Pharmaceutica Nv Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders
AU2007325355A1 (en) 2006-11-28 2008-06-05 Janssen Pharmaceutica N.V. Salts of 3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl) -1,3,8-triaza-spiro[4.5]decan-4-one
US8741916B2 (en) 2007-04-09 2014-06-03 Janssen Pharmaceutica Nv 1,3,8-trisubstituted-1,3,8-triaza-spiro[4.5]decan-4-one derivatives as ligands of the ORL-1 receptor
JP2020519639A (ja) * 2017-05-12 2020-07-02 ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． トリアザスピロ［４．５］デカノンによる胃不全麻痺の処置

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