WO2005094827A1

WO2005094827A1 - Methods for treating sexual dysfunction

Info

Publication number: WO2005094827A1
Application number: PCT/CA2004/000479
Authority: WO
Inventors: Kenneth R. Evans; Terrence L. Sills; Albert Agro; Bruce Dzyngel
Original assignee: Kestrel Pharmaceuticals Inc.
Priority date: 2004-03-30
Filing date: 2004-03-30
Publication date: 2005-10-13

Abstract

The present invention provides methods for treating hypoactive sexual desire disorder, the methods comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound that is a selective agonist at the 5-HT1A receptor. The above methods can be used to treat other sexual disorders in females, including (but not limited to) arousal disorder and orgasmic disorder. Optionally, the above methods can be used to treat male sexual dysfunction, including disorders of desire, arousal and orgasm.

Description

METHODS FOR TREATING SEXUAL DYSFUNCTION

FIELD OF THE INVENTION

The present invention provides methods for treating female hypoactive sexual desire disorder, the methods comprising the step of administering to a female patient in need thereof a therapeutically effective amount of a compound that is a selective agonist at the 5-HTlA receptor. Optionally, the above methods can be used to treat other sexual disorders in females, including (but not limited to) arousal disorder and orgasmic disorder. Optionally, the above methods can be used to treat male sexual dysfunction, including disorders of desire, arousal, and orgasm.

BACKGROUND OF THE INVENTION

It has been estimated that sexual dysfunction may affect as many as 43% of the female population (Laumann et al., 1999) . Primary among the various sexual dysfunctions is a loss of libido, characterized by loss of interest or desire for sexual activity. This is termed "Female Hypoactive Sexual Desire Disorder" (FHSDD) in DSM IV, "Lack or Loss of Sexual Desire" in ICD-10 and "Sexual

Desire Disorder" in the classification system proposed by Basson et al . , 2000. Sexual Desire Disorder (SDD) is generally defined as the "persistent or recurrent deficiency (or absence) of sexual fantasies, and desire for, or receptivity to, sexual activity, which causes personal distress" (Consensus Development Panel on Female Sexual Dysfunction; Basson et al . , 2000). Low or absent sexual desire is highly prevalent, being observed in greater than half of the females that report sexual dysfunction (Laumann et al . , 1999). FHSDD may be lifelong or acquired, and be either a generalized (global) loss of desire or a situational (partner- specific) loss of desire.

Both ICD-10 and DSM-IV draw substantially upon the human sexual response cycle model first described by Masters and Johnson (1966) . This model posits that the human sexual response unfolds in a sequential and coordinated fashion, from sexual desire, to arousal, orgasm and satisfaction. In this regard, sexual response is regarded as a "psychosomatic process" involving both psychological and somatic components .

Currently, no drug has been approved for the indication of FHSDD, hence there is an unmet medical need in the treatment of female sexual dysfunction, especially sexual desire problems .

Evidence from a number of sources suggests that the serotonin 1A (5-HTι_A) receptor may have a role in sexual behaviour. First, stimulation of the 5HTι_A receptor facilitates sexual behaviour in animals (Everaerd and Laan, 2000) . For example, the 5-HT_1A receptor agonists gepirone and ipsapirone facilitate lordosis in estrogen- treated female rodents (Mendelson and Gorzalka, 1986) . Second, the 5-HTι_A agonist gepirone (CINP 2002) and the mixed 5-HT_iA agonist/5-HT_2A antagonist flibanserin (US patent application 20030104980A1) have both been shown to have prosexual effects, particularly enhancing sexual desire. Third, selective 5-HTι_a agonists, including ipsapirone, stimulate the excretion of oxytocin in rodents (Bagdy, 1996; Uvnas-Moberg et al., 1996; Van de Kar et al . , 1998; Vicentic et al . , 1998) and in adult men (Cleare et al . , 1998); oxytocin has been shown to increase sexual receptivity in female rodents (Caldwell et al . , 2000) and to mimic the effects of social contact and enhance sexual receptivity in female prairie voles (Cushing and Carter, 1999) . Fourth, Prozac (a serotonin reuptake inhibitor that enhances availability of serotonin, thereby increasing stimulation of the 5HT_iA receptor) has been reported to cause spontaneous orgasm (Modell, 1989) as well as causing other hypersexual effects in some patients (Balon, 1994) .

SUMMARY OF THE INVENTION

The present invention is based upon the evidence set out above which indicates that drugs that stimulate the 5HT_iA receptor have prosexual effects .

The present invention is therefore directed to a method for treating sexual dysfunction comprising administering to a patient in need thereof a therapeutically effective amount of a compound that is a selective agonist at the 5-HT_1A receptor.

An aspect of the invention relates to the use of a therapeutically effective amount of the compound that is a selective agonist at the 5-HTι_A receptor for treating sexual dysfunction.

Another aspect of the invention relates to the use of a therapeutically effective amount of a compound that is a selective agonist at the 5-HTι_A receptor for the preparation of a medicament for the treatment of sexual dysfunction. In a further aspect of the invention, the sexual dysfunction is female hypoactive sexual desire disorder.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of a selective agonist at the 5-HT_1A receptor for treating sexual dysfunction. In a preferred embodiment, the selective agonist at the 5-HT_iA receptor is for treating female sexual dysfunction. The female sexual dysfunction includes Hypoactive Sexual Desire Disorder, Sexual Arousal Disorder, Failure of Genital Response, or Orgasmic Disorder/Dysfunction. Preferably, the female sexual dysfunction is Hypoactive Sexual Desire disorder characterized by, but not limited to, loss of sexual desire, lack of sexual desire, decreased sexual desire, inhibited sexual desire, loss of libido, libido disturbance or frigidity.

The selective agonist at the 5-HT_1A receptor are those compounds which have activity substantially only against the 5-HTι_A receptor. The selective agonist at the 5-HT_iA receptor are preferably selected from ipsapirone, tandospirone, eptapirone, lesopitron, repinotan, buspirone, flesinoxan, gepirone, alnespirone, VML-670,

MKC 242, OPC-14523, S-15535, and SUN N4057. Particularly preferred 5-HT_1A receptor agonists are ipsapirone or repinotan.

The 5-HTχ_A receptor agonists can optionally be used in the form of their pharmaceutically acceptable acid addition salts. Suitable acid addition salts include those of the acid selected from succinic acid, hydrobromide acid acetic acid fumaric acid maleic acid methane sulfonic acid lactic acid phosphoric acid hydrochloric acid sulfuric acid tartaric acid and citric acid. Mixtures of the acid addition salts may also be used.

The selective agonist at the 5-HT_iA receptor optionally in the form of pharmaceutical acceptable acid addition salts may be incorporated into conventional pharmaceutical preparations in solid, liquid or spray forms. The composition may be presented in the form suitable for oral, rectal, parenteral administration or for nasal inhalation. . These forms may include for example capsules, tablets, coated tablets, ampoules, suppositories and nasal spray. The preferred forms are those for oral administration including capsules, tablets, coated tablets and extended release formulations. The selective agonist at the 5-HT_1A receptor is incorporated in excipients or carriers conventionally used in pharmaceutical compositions such as, for example, talc, arabic gum, lactose, gelatin, magnesium stearate, cornstarch, aqueous or nonaqueous vehicles, polyvinyl pyrrolidone, semi synthetic glycerides of fatty acids, benzalconium chloride, sodium phosphate, EDTA, and polysorbate 80 among others. The compositions are formulated in dosage units, each dosage unit being preferably adapted to supply a single dose of the active ingredient. The dosage range applicable per day will vary depending upon the selective agonist at the 5-HTι_A receptor but in general will be between 0.1 and 200 mg, more preferably between 0.5 and 160 mg.

Suitable tablets may be obtained, for example, by mixing the active substance (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arable, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanilla or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p- hydroxybenzoates .

Solutions for injection are prepared in the usual way, with the addition of preservatives such as p- hydroxybenzoates, or stabilizers such as alkali metal salts of ethylenediamine tetraacetic acid, and transferred into injection vials or ampoules. Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules .

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

The 5-HTi_a agonists are preferably selected from ipsapirone, tandospirone, eptapirone, lesopitron, repinotan, buspirone, flesinoxan, gepirone, alnespirone, VML-670, MKC 242, OPC-14523, S-15535, and SUN N4057. Ipsapirone is a 5-HTlA agonist developed by Bayer and is used at a dosage of 5 to 30 mg per day. Tandospirone has been developed by Sumitomo and is used at a dosage of 5 to 160 mg per day. Eptapirone is a 5-HTι_a agonist developed by Pierre Fabre and is used at a dosage of 1 to 10 mg per day. Lesopitron is a 5-HTχ_a agonist developed by Esteve and is used at a dosage of 5 to 80 mg per day. Repinotan is a 5-HT_la agonist developed by Bayer and is used at a dosage of 0.5 to 10 mg per day. Buspirone is a 5-HTι_a agonist developed by Bristol-Meyers Squibb and is used at a dosage of 10 to 60 mg per day. Flesinoxan is a 5-HTι_a agonist developed by Solvay and is used at a dosage of 1 to 10 mg per day. Gepirone is a 5-HT_la agonist developed by Organon and is used at a dosage of 10 to 80 mg per day. The other agonists, alnespirone developed by Servier, VML-670 developed by Vemalis, MKC 242 developed by Mitsubishi, OPC-14523 developed by Otsuka, S-15535 developed by Servier, and SUN N4057 developed by Suntory are used at the dosage levels generally suitable for their 5-HT_ia agonist activity. The following examples illustrate preferred embodiments of the present invention but are not to be construed as limiting the scope thereof.

EXAMPLE 1 ISAPIRONE

Ipsapirone: 2- (4- (4- (2-pyrimidinyl) -1- piperazinyl) butyl) -1, 2-benzoisothiazol-3 (2H) one 1, 1- dioxide

The preparation of the 2-pyrimidinyl-l-piperazine derivatives is known per se (DE-A 3,321,969) and can take place, for example, by reaction of suitable benzisothiazoles with (piperazinyl) -pyri idines .

The medicaments according to the invention in general contain 1 to 15% by weight, preferably 5 to 10% by weight, of 2-pyrimidinyl-l-piperazine derivatives.

Of course, it is possible that the medicaments according to the invention contain further active compounds known per se.

The medicaments according to the invention may be converted in a known manner into the customary formulations, such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.

The formulations are produced, for example, by extending the active compounds with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, in the case of the use of water as a diluent, organic solvents may be used if appropriate as auxi1iary so1vents .

Auxiliaries which may be mentioned are, for example: water, non-toxic organic solvents, such as paraffins (for example mineral oil fractions) , vegetable oils (for example groundnut/sesame oil) , alcohols (for example ethyl alcohol, glycerol) , excipients, such as, for example, ground natural minerals (for example kaolins, clays, talc, chalk) , ground synthetic minerals (for example highly disperse silica, silicates) , sugars (for example sucrose, lactose and dextrose) , emulsifiers (for example polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, alkylsulphonates and arylsulphonates) , dispersants (for example lignin, sulphite waste liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (for example magnesium stearate, talc, stearic acid and sodium lauryl sulphate) .

Administration takes place in a customary manner, preferably orally, parenterally, perlingually or intravenously. In the case of oral use, tablets may of course also contain additives, such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatin and the like in addition to the said excipients. Furthermore, lubricants, such as magnesium stearate, sodium lauryl sulphate and talc may additionally be used for tabletting. In the case of aqueous suspensions, various flavor-improvers or colorants may be added to the active compounds in addition to the above entioned auxiliaries. EXAMPLE 2 REPINOTAN

Repinotan: 2- [4- ( { [ (2R) -8-isopropoxy-chroman-2- yl]methyl}amino) butyl] -1, 2-benzisothi- azol-3 (2H) -one 1,1-dioxide, its physiologically acceptable salts, hydrates and/or solvates, in particular 2- [4- ( { [ (2R) -8- isopropoxy-chroman-2-yl]met- hyl}amino) utyl] -1, 2- benzisothiazol-3 (2H) -one 1,1-dioxide hydrochloride

Physiologically acceptable salts of the compounds used according to the invention can be salts of the compounds with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are those, for example, with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, oxalic acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Hydrates within the meaning of the invention are stoichiometric compositions of 2- [4 ( { [ (2R) -8-isopropoxy- chroman-2-yl]methyl }amino) butyl] -1, 2-benzisothiazol- 3(2H)-one 1,1-dioxide or its salts with water.

Solvates within the meaning of the invention are stoichiometric compositions of 2- [4- ( { [ (2R) -8-isopropoxy- chroman-2-yl] ethyl}amino)butyl- ] -1, 2-benzisothiazol- 3(2H)-one 1,1-dioxide or its salts with solvents.

The compounds used according to the invention can be prepared by the processes specified in EP-A-0 749 970. For example: 2- [4- ( { [ (2R) -8-isopropoxy-chroman-2- yl]methyl}amino)butyl] -1, 2-benzisothi- azol-3 (2H) -one 1,1-dioxide hydrochloride is prepared according to Example 7 in EP-A-0 749 970.

The salts of 2- [4- ( { [ (2R) -8-isopropoxy-chroman-2- yl]methyl}amino) butyl] -1, 2-benz-isothiazol-3 (2H) -one 1, 1- dioxide can be obtained by reacting the free base in a suitable solvent with stoichiometric or superstoichiometric amounts of the acid on which the salt is based in a temperature range from 0°C. up to the boiling point of the solvent. Suitable solvents are, for example, water, aliphatic alcohols such as ethanol, ethanol or 2-propanol, aliphatic open-chain or cyclic ethers such as diethyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran or , aliphatic ketones such as 2- propanone, 2-butanone, and their mixtures. The salts are obtained directly from this mixture, if appropriate after partially or completely distilling off the solvent, as a solid; they can be purified by recrystallization or reprecipitation in, for example, the abovementioned solvents or their mixtures .

The active compound can act systemically and/or locally. For this purpose, it can be administered in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, transdermally, conjunctivally, otically or as an implant. Administration is preferably carried out orally.

For these administration routes, the active compound can be administered in suitable administration forms. Those suitable for oral administration are known administration forms which release the active compound rapidly and/or in modified form, such as, for example, tablets (non-coated and coated tablets, e.g. enteric coatings) , capsules, sugar-coated tablets, granules, pellets, powders, emulsions, suspensions and solutions.

Parenteral administration can be carried out with avoidance of an absorption step (intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with inclusion of an absorption (intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal) . Suitable administration forms for parenteral administration are, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates and sterile powders .

Forms suitable for other administration routes are, for example, inhalatory pharmaceutical forms (inter alia powder inhalers, nebulizers), nasal drops/solutions, sprays; tablets or capsules to be administered lingually, sublingually or buccally, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures) , lipophilic suspensions, ointments, creams, milk, pastes, dusting powder or implants .

The active compounds can be converted into the administration forms mentioned in a manner per se known. This is carried out using inert non-toxic, pharmaceutically suitable excipients. These include, inter alia, vehicles (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycols) , emulsifiers (e.g. sodium dodecyl sulphate), dispersing agents (e.g. polyvinylpyrrolidone) , synthetic and natural biopolymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), colourants (e.g. inorganic pigments such as iron oxides) or taste and/or odour corrigents .

In a similar manner to the above examples, the other selective agonists at the 5-HT_1A receptor may be formulated and used in the present invention. tandospirone: 3a alpha, 4 beta, 7 beta, 7a alpha- hexahydro-2- (4- (4- (2-pyrimidinyl) -1- piperazinyl) -butyl) -

4, 7-methano-lH-isoindole-l, 3(2H)-dione dihydrogen citrate buspirone: 8- [4- [4- (2-pyrimidinyl) 1-piperazinyl] butyl-8- azaspiro (4,5) -decane-7 , 9-dione lesopitron: 2- (4- [4- (4-chloro-l-pyrazolyl)butyl] -1- piperazinyl) pyrimidine flesinoxan: (+) -N- [2- [4- [2 , 3-dihydro-2- (hydroxymethyl) - 1, 4-benzodioxin-5-yl] -1-piperaz inyl] ethyl] -4- fluorobenzamide hydrochloride gepirone: 4, 4-dimethyl-l- [4- [4- (2-pyrimidinyl) -1- piperazinyl] -butyl] -2, 6-piperidined ione hydrochloride alnespirone: ( (+) (4- [N- (5-methoxychroman-3yl)N- propylamine] butyl) -8-azaspirol [4,5] decane-7, 9-dione) Eptapirone: 4-methyl-2- [4- [4- (2-pyrimidinyl) -1- piperazinyl] butyl] -as-triazine-3, 5 (2H, 4H) -dione MKC-242: 5-(3-[ [ (2S) -1, 4-benzodioxan-2- ylmethyl) ] amino]propoxy) -1, 3-b enzodioxole HCl OPC-14523 : 1- [3- [4- (3-chlorophenyl) -1- piperazinyl] propyl] -5-methoxy-3, 4-dihydro-2 [1H]- quinolinone monomethanesulfonate

S-15535: ^• 4- (benzodioxan-5-yl) 1- (indan-2- yl)piperazine SUN N4057: 3-chloro-4- [4- [4- (2-pyridinyl) -1 , 2 , 3 , 6- tetrahydropyridin-1-yl]butyl] -1, 4-benzoxazepin-5 (4H) -one The present invention may also be used in the treatment of certain male sexual dysfunctions, including, but not limited to, Hypoactive Sexual Desire Disorder, Orgasmic Disorder/Dysfunction or Erectile Disorder/Dysfunction. These disorders are treated in a similar manner as for the female sexual dysfunction.

Although various preferred embodiments of the present invention have been described herein in detail, it will be appreciated by those skilled in the art that variations may be made thereto without departing from the spirit of the invention or the scope of the appended claims .

Claims

WE CLAIM :

1. Use of a selective agonist of the 5-HTι_A receptor for the treatment of female sexual dysfunction.

2. Use of claim 1 wherein the selective agonist of the 5-HTι_A receptor is selected from the group consisting of ipsapirone, tandospirone, eptapirone, lesopitron, repinotan, buspirone, flesinoxan, gepirone, alnespirone, VML-670, MKC 242, OPC-14523, S-15535, and SUN N4057.

3. Use of claim 2 wherein the female sexual dysfunction is Hypoactive Sexual Desire Disorder, Sexual Arousal f

Disorder, Failure of Genital Response, or Orgasmic Disorder/Dysfunction.

4. Use of claim 3 wherein the female sexual dysfunction is Hypoactive Sexual Desire Disorder.

5. Use of claim 4 wherein the Hypoactive Sexual Desire disorder includes loss of sexual desire, lack of sexual desire, decreased sexual desire, inhibited sexual desire, loss of libido, libido disturbance or frigidity.

6. Use of claim 4 wherein the 5-HT_1A receptor is selected from ipsapirone and repinotan.

7. Use of a selective agonist of the 5-HT_1A receptor selected from ipsapirone, tandospirone, eptapirone, lesopitron, repinotan, buspirone, flesinoxan, gepirone, alnespirone, VML-670, MKC 242, OPC-14523, S-15535, and SUN N4057 for the treatment of male sexual dysfunctions selected from Hypoactive Sexual Desire Disorder, Orgasmic Disorder/Dysfunction and Erectile Disorder/Dysfunction.

8. Use of a selective agonist of the 5-HT_1A receptor for the preparation of a medicament for the treatment of female sexual dysfunction.

9. Use of claim 8 wherein the selective agonist of the 5-HTι_A receptor is selected from the group consisting of ipsapirone, tandospirone, eptapirone, lesopitron, repinotan, buspirone, flesinoxan, gepirone, alnespirone, VML-670, MKC 242, OPC-14523, S-15535, and SUN N4057.

10. Use of claim 9 wherein the female sexual dysfunction is Hypoactive Sexual Desire Disorder, Sexual Arousal Disorder, Failure of Genital Response, or Orgasmic Disorder/Dysfunction.

11. Use of claim 10 wherein the female sexual dysfunction is Hypoactive Sexual Desire Disorder.

12. Use of claim 11 wherein the Hypoactive Sexual Desire disorder includes loss of sexual desire, lack of sexual desire, decreased sexual desire, inhibited sexual desire, loss of libido, libido disturbance or frigidity.

13. Use of claim 11 wherein the selective agonist of the 5-HTι receptor is selected from ipsapirone and repinotan.

14. A method for treating female hypoactive desire disorder comprising the step of administering to a female patient in need thereof a therapeutically effective amount of a compound that is a selective agonist at the 5-HTlA receptor.

15. The method of claim 14 wherein the selective agonist of the 5-HT_iA receptor is selected from the group consisting of ipsapirone, tandospirone, eptapirone, lesopitron, repinotan, buspirone, flesinoxan, gepirone, alnespirone, VML-670, MKC 242, OPC-14523, S-15535, and SUN N4057.

16. The method of claim 15 wherein the female sexual dysfunction is Hypoactive Sexual Desire Disorder, Sexual Arousal Disorder, Failure of Genital Response, or Orgasmic Disorder/Dysfunction.

17. The method of claim 16 wherein the female sexual dysfunction is Hypoactive Sexual Desire Disorder.

18. The method of claim 17 wherein the Hypoactive Sexual Desire disorder includes loss of sexual desire, lack of sexual desire, decreased sexual desire, inhibited sexual desire, loss of libido, libido disturbance or frigidity.

19. The method of claim 17 wherein the selective agonist of the 5-HTι_A receptor is selected from ipsapirone and repinotan.

20. A method for treating male sexual dysfunctions selected from Hypoactive Sexual Desire Disorder, Orgasmic Disorder/Dysfunction and Erectile Disorder/Dysfunction comprising the step of administering to a male patient in need thereof a therapeutically effective amount of a compound that is a selective agonist at the 5-HTIA receptor, the compound selected from ipsapirone, tandospirone, eptapirone, lesopitron, repinotan, buspirone, flesinoxan, gepirone, alnespirone, VML-670, MKC 242, OPC-14523, S-15535, and SUN N4057.