CA2167842A1 - Method of inhibiting the replication of human immunodeficiency viruses with substituted azaspiranes - Google Patents

Abstract

Invented is a method of inhibiting the replication of human immunodeficiency viruses (HIV) in HIV seropositive humans which comprises administering to such human an effective amount of a substituted azaspirane.

Description

WO 95/03042 PCT/US94tO8276 METHOD OF INHIBITING THE REPLICATION OF HUMAN IMMUNODEFICIENCY
VIRUSES WITH SUBSTITUTED AZASPIRANES
lllis invention relates to a method of inhibiting the replication of human immnnodefisiency viruses (HIV) in HIV seropositive humans which comprises ~lminicte,ring to such human an effective amount of a sub~ uled azaspirane.
s Back~round of the Invention Nu~ r~us agents are pl~senlly available which inhibit the repliration of hurnan immvnodrficiensy viruses in T cells and monocytes (Yarchoan et al., Lancet (1986); 1:575-580 and Broder et al., lancet (1985); ~:627-630). These 10 colll~oullds are limited in their usefulness due to significan~ toxicities and viral recictance Acsoci~ated with their long-term use Volberding, et al., N. Fn~l J. Med 1990; 322:941-949. ~drlitionally~ certain selected imml~nosulJyl~ssi~efimmllnomodlll~a~tory agents have demonstrated an ability to Suyyl~SS viral replication Specifically, immllnom~Anlating CD8 lymphocytes 15 have been shown to ~Uy~l.,ss replication of HIV in peripheral blood mononuclear cells (WaLker et al. Science. ~:1563-6 (1986)) and activated CD8+ T cells have been shown to inhibit the repliration of HIV in cultures of CD4+ cells from a~ll t~ atic HIV se,upo~ re individuals (I3l;nc~ n et al. CD8+ T cells L
I.. n-ol. 144 2961-2966 (1990)). Further, the imm~nosuy~i,si~re co~ ,oul~d 20 cyclosporin A (CsA) has Aemonct ated a ~lotecli~/e effect in several animal models of viral infection Particularly, chronic treatment with CsA before and after infe~tion with LP-BM5 murine lellkemia. virus has proven effective againstthe dcvelopl.. ~-nl of .. ~ ~o~lefirie-ncy disease (Cerny, A. et al. F.nr J. Jl-l.. -ol.
~:1747-50 (1991)). Evidence that ~ ... .t of AlDS and HIV-s~ osi~ e non-25 AIDS ~I;r--l~ with CsA i,l.,l~ases T4 cells and inhibits l~ ,haA~,-opathy has also been ~lJUlt~d. (Andrieu et al. Clin. Immunol. and Illlnlulllu~)alllol. ~:181-198(1988)). However, none of the above references suggest that ;Illll~u~osyll~lessev~l~llllu~lrJmn~ul~tory agents in general will have utility in inhibitin~ HIV repliration in HIV se-oposili-/e humans Further, none of the 30 above r~Çe,~nces teaches or S~lggeSt a means for predicting whether a particular .os~ s~ e/;~ .no..~nd~la~to~r agent will have utility in inhibiting HIV
replir~tiQn in H~V s~n")o~ e hllman~
Badger, et al., U.S. Patent No. 4,963,557 (Badger I) ~liscloses coll,~,ounds of the formula WO 95/0304~ 2 t ~ 7 8 4 ~ PCT/US94/08276 R2/ / (CH2)m N \ N ~R3 R4 (I) wL~,in: n is 3-7; m is 1 or 2; Rl and R2 are the same or different and are selected from hydrogen or straight or branched chain alkyl, provided that the total number of carbon atoms cont~ined by Rl and R2 when taken together is 5-10; or Rl and 5 R2 together form a cyclic alkyl group having 3-7 carbon atoms; R3 and R4 are the same or dirrcl~inl and are selecte~ from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R3 and R4 are joined together with the nitrogen atom to form a hete..cyclic group having 5-8 atoms; or a ph~rm~ceutically acceptable salt or hydrate or solvate thereof.
Badger I rliscloses coml)ounds of Formula I as a class of novel compounds which induce an immllnomodnl~tory effect which is characterized by the stimul~tion of SU~ 550r cell activity.
Badger I does not ~ii~lose the con~l)ounds of Formula I as agents for inhibiting HIV renlication in HIV scr~yo~ ve hllm~n~
Sunllnal~ of the Invention This invention relates to a method of inhibiting HIV replication in HIV
sc~posi~i-/e hnm~ns which comprises a~ministering to such human an effective a~unt of a compoulld of the formula Fy~(c R ~/ 2 m \ (CH2)n N \
R4 (I) wl~lcin:
nis3-7;
mis 1 or2;
R1 and R2 are the same or dirr~ t and are selected from hydrogen or 25 straight or blanched chain alkyl, provided that the total number of carbon atoms conl~inPA by Rl and R2 when taken together is 5-10; or R1 and R2 together form a cyclic aL~yl group having 3-7 carbon atoms;
R3 and R4 are the same or dirr~.~nt and are selected from hydrogen or straight chain aLkyl having 1-3 carbon atoms; or R3 and R4 are joined together 30 with the nitrogen atom to form a heterocyclic group having S-8 atoms;

wo 95/03042 2 1 6 7 8 4 2 PCT/US94/08276 or a pharrn~reutic~lly acceptable salt or hydrate or solvate thereof.

Det~iled Description of the Invention The ~çtpala~ion of all compounds of Formula (I) and pharmaceutically 5 ~ccept~hle salts, hydrates and solvates and formulations thereof is disclosed in U.S. Patent No. 4,963,557, the entire disclosure of which is hereby incul~olat~dby reference.
A prefc.l~,d co.--po~ A used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R 1 and R2 are propyl, R3 and R4 are methyl, 10 m is 1 and n is 3 which is N,N-dimethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2- pl~zllli.~ dihydrochloride.
A particularly p~ ,d compound used in the novel method is the dihydrochloride salt of a compound of Forrnula (I) where Rl and R2 are propyl, R3 and R4 are ethyl, m is 1 and n is 3 which is N,N-diethyl-8,8-dipropyl-2-15 azaspiro[4.5~decane-2-prop~n~mine dihydrochloride.
A particularly pltfell~d compound used in the novel method is the dihydrochlQride salt of a coln~,ound of Formula (I) where R1 and R2 are propyl, R3 and R4 are joined together with the nitrogen to form a piperidine ring, m is 1 and n is 3 which is 8,8-dipropyl-2-azaspiro[4.5]decane-2-piperidinopropyl 20 dihyd,~.chloride.
This invention discloses compounds of Formula (I) and l~h~ reutir~lly acceptable salts or hydrates or solvates thereof as being useful for inhjbiting HIV
replication in HIV seropositive hnm~n~
The colll~ounds of Formula I are tested for their ability to inhibit HIV
25 replic~tior in the assay described in Sperber, et al., AIDS Research and Human Retrovituses. 2 No.l, 91-98.
This invention relates to a method of inhibiting HIV replication which comprises ~imini~tering to an HIV s~lol~osi~-~e human an effective ~mount of a coull)ol~nd of Forrnula (I) or a ph~...~cetltic~lly acceptable salt or hydrate or 30 solvate thereof. A compound of Forrnula (I) or a pharrn~reu~iczlly- acceptable salt or hydrate or solvate thereof can be ~lminist~-red to such human in a convention~l dosage forrn l,~p~,d by combining a compound of Formula (I) or a phz....z~t~.l;r-ally ~ccept~hle salt or hydrate or solvate thereof, with a conventiQn~l ph~~ r-e.ll;c~lly acceptable carrier or diluent according to known " 35 techniques, such as those described in Badger (I), 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 pharm~reutic~lly acceptable carrier or diluent is dictated by the arnount of - 3 ^

wo gs/03042 2 1~ 6 7 8 4 ~ PCTtUS94tO8276 active ingredient with which it is to be combined, the route of aAministration and other well-known variables. A compound of Formula (I) ("Active Ingredient") or a pharm~e~ltic~lly acceptable salt or hydrate or solvate thereof is a~lminictered to an HIV seropositive human in an amount sufficient to inhibit S HIV replication The route of nAminictration of the Formula (I) co~ )ol~nd is not critical but is usually oral or ~arentel~l, preferably oral.
The term pal~,llt~ l as used herein includes intravenous, in~ .SC~ r, su~v~ r~us~ inL~ asal, i~ al~,ctill, transdermal, intravaginal orinL.~l,e.;to 10 ~lminictration. The subcu~leolls and in~lA...~scul~r forms of p~;,ltel~l ~rlminictr~tion are generally ~l~;fell~d. The daily l,alenl~lal 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~cg to about 1 mg/lcg. Preferably, each al dosage unit will contain the active ingredient in an amount of from about 0.1 mg to about 100 mg.
The compounds of Formula (I) which are active when given orally can be form-~l~ted as liquids, for example syrups, suspensions or emulsions, tablets, c~psules and 107enges A liquid formulation will generally consist of a sUcpencion or soh-tion of the 20 collll)ound or ph~~ eutic~lly acceptable salt in a s--it~ble liquid carrier(s) for eY~mple, eth~nol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a s~lspen-ling agent, preservative, flavoring or coloring agent.
A co."~ilion in the form of a tablet can be pç~ed using any suitable phd~ e.,~ l carrier(s) routinely used for pl.,~ g solid form~ tio~c Fy~mples 25 of such caIriers include m~ es;u~ stearate, starch, lactose, sucrose and celll~lose A composition in the form of a capsule can be ~ d using routine en~ tion procedures. For example, pellets co~ ning the active ingredient can be p.~p~r~ using standard carriers and then filled into a hard gelatin c~ps.lle alternatively, a dispersion or s~lspencion can be ~I~,pal.,d using any suit~ble 30 ph~ ~ r~ul ;c~l ca~ier(s), for example aqueous gums, celluloses, silic~tes 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 unit will contain the active ingredient in an amount of from about 0.1 mg to about 100 35 mg.
While it is possible for an active ingredient to be a~lmini~tered alone, it is preferable to present it as a pharm~eutical formulation.

wo 95/03042 2 1 6 7 8 4 2 PCT/US94/08276 It will be recognized by one of skill in the art that the optimal quantityand spAcing of individual dosages of a compound of formula (I) or a l,h~lllaceutically 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 5 of ~lminictruion, and the particular patient being treated, and that such OplilllUIllS can be deterrnined by conventional techniques. It will also be ; appreciated by one of skill in the art that the optimal course of treatm~nt, i.e., the number of doses of a cc"ll~ound of Formula (I) or a phalll.Ace~ Ally acceptable salt or hydrate or solvate thereof given per day and duration of 10 therapy, can be ascertained by those skilled in the art using conventional course of ~ ,nt determin~tion tests.
The method of this invention of inhibiting HIV replication in HIV
seropositive hllm~nc colll~l;ses ~minictering to a subject in need of such inhibition an effective HIV replication inhibiting amount of a pha~...AceulicAlly active 15 cc,ll~pound of the present invention.
The invention also provides for the use of a compound of Formula (I) in the m~nllfacture of a mPAir~m~nt for use in inhibiting HIV replication in HIV
S~.~Oposili.,re hum~nc The invention also provides for a pharmaceutical composition for use 20 inhibiting HIV replir~tiQn in HIV scl~osili~e humans which comprises a c....~...~d of Formula I and a ph~...~c~.ll;c~lly acceptable carrier.
The invention also provides for a process for preparing a ph~ . .~CP~ ;r~l co~ ,osilion cont~;ning a pha~ re~ltic~lly acceptable carrier or diluent and a compound of Formula I which comprises bringing the col~ oLwld of Formula I into 25 ~ccoci~tion with the ph~---~reutir~lly acceptable carrier or diluent.
No un~ccept~bIc toxicological effects are e~ecled when colllpounds of the invention are arlminist~p~red in accor~ance with the present invention.
In addition, the cc.lllpoùnds of the present invention can be co-a~lminictered with further active in~cA;P,..I~ such as collll)o~ ds known to prevent or delay the 30 oc~ llce of AIDS in HIV seropositive humans such as retrovir (the brand name for zidovudine, folln~,lly called azidothymidine (AZT)).
Without further elaboration, it is believed that one skilled in the art can, using the l,lcc~l;.-g des~"lp~ion, utilize the present invention to its fullest extent.
The following eY~mples are, t}lc.efc~le, to be construed as merely illustrative and 35 not a limit~tion of the scope of the present invention in any way.

FxAMpI F l - CAPSULE COMPOSITION

Wo 95to3042 2 1 ~ 7 a 4 ~ PCT/US94/08276 An oral dosage form for ~dminictering Formula (I) compounds is produced by filing a standard two piece hard gelatin capsule with the ingredients in the l,lopolLions shown in Table I, below.

Table I
I~G~F.l )~F.NTS AMOUNTS
N,N-diethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2- 25 mg prop~r~mine dihydrochloride ~ ~tose 55 mg Talc 16 mg ~g.lf i,h.,~. Stearate 4 mg F.XAMP~ .F. 2 - rNJECI AB~ .F PARENTERAL COMPOSITION
An injectable form for ~r1minictçring Formula (I) compounds is produced by stirring 1.5% by weight of N,N-diethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2-10 plup~n~ ;ne dihydrochloride in 10% by volume propylene glycol in water.
FY~ml?le 3 - Tablet Co,l"~osiLion The sucrose, calcium sulfate dihydrate and Formula (I) colllpound shown in Table II below, are mixed and gr~n~ e~ in the pr~pol LionS shown with a 10%
15 gelatin sdution. The wet granules are s.;l~enf d, dried, mixed with the starch, talc and stearic acid, s.,lec"ed and co"lpl~ssed into a tablet.

Table II
In~redients Amollntc N,N-diethyl-8,8-dipropyl-2-azaspiro[4,5]decane- 20 mg 2-prop~n~mine dihydrochloride c~lrium sulfate dihydrate 30 mg sucTûse 4 mg starch 2 mg talc 1 mg stearic acid 0.5 mg While the above des"il~Lions and ex~mrles fully describe the invention and the ~,~ef~ d embod;~f, ~t~ thereof, it is understood that the invention is not limited to the particular disclosed f~mborlimf.nt.c coming within the scope of the following claims.

Claims (6)

What is claimed is:

1. Use of a compound of the formula (I) wherein:
n is 3-7;
m is 1 or 2;
R1 and R2 are the same or different and are selected from hydrogen or straight or branched chain alkyl, provided that the total number of carbon atomscontained by R1 and R2 when taken together is 5-10; or R1 and R2 together form a cyclic alkyl group having 3-7 carbon atoms;

R3 and R4 are the same or different and are selected from hydrogen or straight chain alkyl having 1-3 carbon atoms; or R3 and R4 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; in the manufacture of a medicament for inhibiting the replication of human immunodeficiency viruses (HIV) in HIV seropositive humans.

2. The use according to 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.

3. The use according to claim 1 wherein the compound is administered orally.

4. The use according to claim 3 wherein from about 0.01 mg/kg to about 10 mg/kg of compound is administered per day.

5. The use according to claim 1 wherein the compound is administered parenterally.

6. The use according to claim 5 wherein from about 0.01 mg/kg to about 10 mg/kg of compound is administered per day.