AU666175B2 - A method for delaying HIV induced AIDS by administration of substituted azasperane compounds - Google Patents

Description

LORLECJED

VERSSKION

I

revised title received by the international Bureau after completion of the technical preparations for international PUI publication INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 93/14760 A61K 31/55, 31/455 31/40 A3 (43) International Publication Date: 5 August 1993 (05.08.93) (21) International Application Number: PC '!S93/00730 (81) Designated States: AU, CA, JP, KR, US, European patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, (22) International Filing Date: 27 January 3 (27.01.93) MC, NL, PT, SE).

Priority data: Published 9201803.5 28 January 1992 (28.01.92) GB With international search report.

Before the expiration of the time limit for amending the claims and to be republished in the event of the receipt of (71) Applicant (for all designated States except US): SMITH- amendments.

KLINE BEECHAM CORPORATION [US/US]; One Franklin Plaza, P.O. Box 7929, Philadelphia, PA 19101 (88) Date of publication of the.international search report: 2 September 1993 (02.09.93) (72) Inventor; and Inventor/Applicant (for US only): BADGER, Alison, Mary [US/US]; 56 Parkridge Drive, Bryn Mawr, PA 19010

(US).

(74) Agents: DUSTMAN, Wayne, J. et al.- SmithKline Beecham Corporation, Corporate Patent, U.S. UW2220, 709 Swedeland Road, P.O. Box 1538, King of Prussia, PA 19406-0939 (US).

(54) Title: A METHOD FOR DELAYING IIIV INDUCED AIDS BY ADMINISTRATION OF SUBSTITUTED AZASPERANE COMPOUNDS (57) Abstract Invented is a method of preventing or delaying the occurrence of acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus (HIV) seropositive humans which comprises administering to such human an effective therefor amount of a substituted azaspirane.

(Referred to in PUT (i U ete No. 21/)93. Section, II) WO 93/147960 PCT/US93/00730 1

METHODS

This invention relates to a method of preventing or delaying the occurrence of acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus (HIV) seropositive humans which comprises administering to such human an effective therefore amount of a substituted azaspirane.

Background of the Invention The use of immunosuppressive/immunomodulatory agents has been shown to suppress viral replication.

Specifically, immunomodulating CD8 lymphocytes have been shown to suppress replication of HIV in peripheral blood mononuclear cells (Waler et al. Science, 234:1563-6 (1986)) and activated CD8+ T cells have been shown to inhibit the replication of HIV in cultures of CD4+ cells from asymptomatic HIV seropositive individuals (Brinchmann et al. CD8+ T cells J. Immunol.

14A 2961-2966 (1990)). Further, the immunosuppressive compound cyclosporin A (CsA) has demonstrated a protective effect in several animal models of viral infection. Particularly, chronic treatment with CsA before and after infection with LP-BM5 murine leukemia virus has proven effective against the development of immunodeficiency disease (Cerny, A. et al. Eur. J.

Immunal 21:1747-50 (1991)). Evidence that treatment WO 93/14760 PCT/US93/00730 2 of AIDS and HIV-seropositive non-AIDS patients with CsA increases T4 cells and inhibits lymphadenopathy has also been reported. (Andrieu et al. Clin. Immunol. and Immumopathol. A4:181-198 (1988)).

Badger, et al., U.S. Patent No. 4,963,557 (Badger I) discloses compounds of the formula

(CH

2 n

N-

R4

(I)

wherein: n is 3-7; m is 1 or 2; R 1 and R 2 are the same or different and are selected from hydrogen or straight or branched chain alkyl, provided that the total number of carbon atoms contained by R 1 and R 2 when taken together is 5-10; or R 1 and R 2 together form a cyclic alkyl group having 3-7 carbon atoms; R 3 and R 4 are the same or different and are selected from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R 3 and

R

4 are joined together with the nitrogen atom to form a heterocyclic group having 5-8 atoms; or a pharmaceutically acceptable salt or hydrate or solvate thereof.

Badger I discloses compounds of Formula I as a novel class of compounds which induce an immunomodulatory effect which is characterized by the stimulation of suppressor cell activity.

Badger I does not disclose the compounds of Formula I as agents for preventing or delaying the occurrence of AIDS in HIV seropositive humans.

WO 93/14760 PCT/US93/00730 Summary of the Invention This invention relates to a method of preventing or delaying the occurrence of AIDS in HIV seropositive humans which comprises administering to such mammal an effective therefor amount of a compound of the formula 1 2

/R

3 R2 N

(CH

2 N R4 (I) wherein: n is 3-7; m is 1 or 2;

R

1 and R 2 are the same or different and are selected from hydrogen or straight or branched chain alkyl, provided that the total number of carbon atoms contained by R 1 and R 2 when taken together is 5-10; or

R

1 and R 2 together form a cyclic alkyl group having 3-7 carbon atoms;

R

3 and R 4 are the same or different and are selected from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R 3 and R 4 are joined together with the nitrogen atom to form a heterocyclic group having 5-8 atoms; or a pharmaceutically acceptable salt or hydrate or solvate thereof.

Detailed Description of the Invention The preparation of all compounds of Formula (I) and pharmaceutically acceptable salts, hydrates and solvates and formulations thereof is disclosed in U.S.

Patent No. 4,963,557, the entire disclosure of which is hereby incorporated by reference.

A preferred compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) WO 93/14760 PCT/US93/00730 4 where R 1 and R 2 are propyl, R 3 and R 4 are methyl, m is 1 and n is 3 which is N,N-dimethyl-8,8-dipropyl-2azaspiro[4,5]decane-2-propanamine dihydrochloride.

A preferred compound used in the novel method is a compound of Formula where R 1 and R 2 are propyl, R 3 and R 4 are ethyl, m is 1 and n is 3 which is N,Ndiethyl-8,8-dipropyl-2-azaspirof4,5]decane-2propanamine and salts thereof.

This invention discloses compounds of Formula (I) and pharmaceutically acceptable salts or hydrates or solvates thereof as being useful for preventing or delaying the occurrence of AIDS in HIV seropositive humans.

This invention relates to a method of delaying or preventing the occurrence of AIDS which comprises administering to an HIV seropositive human an effective therefor amount of a compound of Formula (I) or a pharmaceutically acceptable salt or hydrate or solvate thereof. A compound of Formula or a pharmaceutically acceptable salt or hydrate or solvate thereof can be administered to such human in a conventional dosage form prepared by combining a compound of Formula or a pharmaceutically acceptable salt or hydrate or solvate thereof, with a conventional pharmaceutically acceptable carrier or diluent according to known techniques, such as those described in Badger U.S. Patent No. 4,963,557.

It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other wellknown variables. A compound of Formula or a WO 93/14760 PCT/US93/00730 5 pharmaceutically acceptable salt or hydrate or solvate thereof is administered to an HIV seropositive human in an amount sufficient to prevent or delay the occurrence of AIDS.

The route of administration of the Formula (I) compound is not critical but is usually oral or parenteral, preferably oral.

The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, intranasal, intrarectal, transdermal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. The daily parenteral dosage regimen will preferably be from about 0.01 mg/kg to about 10 mg/kg of total body weight, most preferably from about 0.1 mg/kg to about 1 mg/kg. Preferably, each parenteral dosage unit will contain the active ingredient in an amount of from about 0.1 mg to about 100 mg.

The compounds of Formula which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) WO 93/14760 PCT/US93/00730 6 routinely used for preparing solid formulations.

Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

The daily oral dosage regimen will preferably be from about 0.01 mg/kg to about 10 mg/kg of total body weight. Preferably each oral dosage u.it will contain the active ingredient in an amount of from about 0.1 mg to about 100 mg.

While it is possible for an active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation.

It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of formula or a pharmaceutically acceptable salt or hydrate or solvate thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, the number of doses of a compound of Formula or a pharmaceutically acceptable salt or hydrate or solvate thereof given per day and duration WO 93/14760 PCT/US93/00730 of therapy, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

In addition, the compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to prevent or delay the occurrence of AIDS in HIV seropositive humans such as retrovir (the brand name for zidovudine, formerly called azidothymidine (AZT)).

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

EXAMPLE 1 CAPSULE COMPOSITION An oral dosage form for administering Formula (I) compounds is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table I, below.

fTable I INGREDIENTS AMQUNTS N,N-dimethyl-8,8-dipropyl-2- 25 mg azaspiro[4,5]decane-2-propanamine dihydrochloride Lactose 55 mg Talc 16 mg Magnesium Stearate 4 mg EXAMPLE 2 INJECTABLE PARENTERAL COMPOSITION WO 93/14760 PC'1US93/0730 8 An injectable form for administering Formula (I) compounds is produced by stirring 1.5% by weight of N,N-dimethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2propanamine dihydrochloride in 10% by volume propylene glycol in water.

Example 3 Tablet Composition The sucrose, calcium sulfate dihydrate and Formula compound shown in Table II below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.

Table II Ingredients Amounts N,N-diethyl-8,8-dipropyl-2- 20 mg azaspiro[4,5]decane-2-propanamine dihydrochloride calcium sulfate dihydrate 30 mg sucrose 4 mg starch 2 mg talc 1 mg stearic acid 0.5 mg While the above descriptions and examples fully describe the invention and the preferred embodiments thereof, it is understood that the invention is not limited to the particular disclosed embodiments coming within the scope of the following claims.

Claims (2)

1. A method for preventing or delaying the occurrence of acquired immunodeficiency syndrome (AIDS) in human immumodeficiency virus (HIV) seropositive humans which comprises administering to such human an effective therefor amount of a compound of the formula 1 R (CH 2 N/ R4 wherein: n is 3-7; m is 1 or 2; R 1 and R 2 are the same or different and are selected from hydrogen or straight or branched chain alkyl, provided that the total number of carbon atoms contained by R 1 and R 2 when taken together is 5-10; or R 1 and R 2 together form a cyclic alkyl group having 3- 7 carbon atoms; R 3 and R 4 are the same or different and are selected from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R 3 and R 4 are joined together with the nitrogen to form a heterocyclic group having

5-8 atoms; or a pharmaceutically acceptable salt or hydrate or solvate thereof. 2. The method of claim 1 wherein the compound is N,N-diethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2- propanamine; or a pharmaceutically acceptable salt, hydrate or solvate thereof. 10 3. The method of claim 1 wherein the compound is administered orally. 4. The method of claim 3 wherein from about 0.01 mg/kg to about 10 mg/kg of compound is administered per day. The method of claim 1 wherein the compound is administered parenterally. 6 The method of claim 5 wherein from about 0.01 mg/kg to about 10 mg/kg of compound is administered per day. Dated this 22nd day of November, 1995 SmithKline Beecham Corporation By its Patent Attorneys, Davies Collison Cave e :e *o 951 122,q:\opcr\jms,35951.po.326,10 INTERNATIONAL SEARC1H REPORT Intern~ationlal application No, PCT/US93/00730 A. CLASSIFICATION OF SUBJECT MATTER :A61K, 3 1155; 31/455; 31/40 US CL :514/212,320,407 According to International Patent Classification (IC) or to both national classification and IPC B. FIELDS SEARCHED Minimum dccumentation searched (classification system followed by classification symbols) U.S. Documentation searched other tha~n minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during thc international search (name of data base and, where practicable, search terms used) STN-Beilstein-compound antival use C. DOCUMEFNTS CONSIDERED TO BE RELEVANT Category's Citation of document, with indic- where appropriate, of the relevant passages Relevant to claim No. See attached sheet D Further documents are listed in the continuation of Bon C. See patent family annex. Specia csleorics of ekted docan: -r a dccumew pubiiliewd after the ituetusrional filing daste or priorty date sad not in confict with the seplication but cited to wdtt h W docuamentdeining the general owae ol tho ani which is amt ponaidetul or theory aideutying the gavuadon 'be pant of Pamticular relevance catter oa~ubt~laa onor i~e ~e mmtoes W docuant of ~iairreleveant tbe claimed invention cannot be earierdocmempubishd o oraftr de ia ustinalfilng we ocujidend erwel or cannot be considered to itnvolve an invenive c U documinat which nay throw doubts on priorty claim(s) or which. iswhn document istakes slow ctud to eutabLish the publication d4s-e of anotber citation or other Y special rean (as spocifiedi) 'Y docuimaat of petticuter relvanc; the claimed invention cannot be considered to skvolv- an inventive step whev ve document is .0 docmen referinag to an oat disclosr, use, exhibition or other combined with one or cuore other mobi dociaianj-a ,ucb ombinciton being obvious to a person skilled in the an document published prior to the iaxeentins filing daue but lawe than documnt memer of the same patent family the priority date clhus- Date of the actual completion of the international. search Date of mailing of the international search report 27 APRIL 1"93 08 JUL 1993 Name and mailing address of the ISAIUS Authorized officer W 4 /j Commissioner of Patents and Trademarks 0 Box PCTr''Y-USL TRAvER S Washington, D.C. 20231 SSL Facsimile No. NOT APPLICABLE Telephone No. (703) 308-1235 Form PC'l'ISAJ21O (second shect)(July IM9),i PCT/US93/00730 category citation to document cla ims Y Chemical Abstracts, Volume 12.3, no. 21, 13-18 issued 1990, November 19, (Columbus, Ohio., Badger et al., Antiarthritic and suppressor cell inducing activity-of azaspiranes: structure- function relationships of a novel class of imniunomodulatory agents. (Dept. Immumal., SmithKline ain-dFrench Lab., King of Prussia, PA 19406-0939 USA) J. Med. Chem. 1990, 33(11), pp. 2963-70., -the abstract no. 191085r. Y Chemical Abstracts, Volume 111, no. 17, 13-18 issued 1989, October 23, (Columbus, Ohio, Badger et al., Preparation of N-aminoakyl-2-azaspirof4.5]decanes and analogs as imxnunosuppressants. (Dept. Immuuiol., SmithKline Beckmann corp., King of Prussia, PA 19406-0939 USA) Eur. Pat. Appi. PE31O,321 (Cl A61K31/40), 05 April 1989, US Appl. 101,704 28 Sep 1987; 39pp., the abstract no. 153616r. Y Chemical Abstracts, Volume 86, no. 9, 13-18 issued 1977, February 28 (Columbus, Ohio, El-Telbany et al., Synthesis of-certain spiro compounds for pharmacological study. Part III (Fac. Pharm., Cairo, Egypt). J. Pharm Belg. 1976, 31(4, pp 403-10. the abstract no. 55229n. INTERNATIONAL SEARCH REPORT International application No. PCT/US93/00730 Box I Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet) This international report has not been established in respect of certain claims under Article 17(2XL) for the following reasons: 1. Claims Nos.: Sbecause they relate to subject matter not required to be searched by this Authority, namely: 2. F[ Claims Nos.: Sbecause they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: 3. O Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international, application, as follows: (Telephone Practice) See attached sheets. 1. As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims. 2. As all searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3. O As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.: 4. O No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: Remark on Protest The additional search fees were accompanied by the applicant's protest. SNo protest accompanied the payment of additional search fees. Form PCT/ISA/210 (continuation of first sheet(l))(July 1992)*