CA2167841A1 - Method of inhibiting the production of human immunodeficiency viruses with substituted azaspiranes - Google Patents
Method of inhibiting the production of human immunodeficiency viruses with substituted azaspiranesInfo
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- CA2167841A1 CA2167841A1 CA002167841A CA2167841A CA2167841A1 CA 2167841 A1 CA2167841 A1 CA 2167841A1 CA 002167841 A CA002167841 A CA 002167841A CA 2167841 A CA2167841 A CA 2167841A CA 2167841 A1 CA2167841 A1 CA 2167841A1
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- hiv
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- 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
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Invented is a method of inhibiting the production of infectious human immunodeficiency viruses (HIV) in HIV seropositive humans which comprises administering to such human an effective amount of a substituted azaspirane.
Description
W O 95/03041 PCTrUS94/08275 METHOD OF INHIBITING THE PRODUCTION OF HUMAN IMMUNODEFICIENCY
VIRUSES WITH SUBSTITUTED AZASPIRANES
This invention relates to a method of inhibiting the protl.~ction Of il~rcc!io~ human ;~l~ln~ ~erlriency viruses (HIV) in HIV s~,.u~,o~ /e hnm~n~
which comprises r ~minicterin~ to such human an effective amount of a su~
5 ~?~U~C.
R~rL ~.o.~ntl of the Inverltion Nu~ wuus agents are yl~;s~ ~tly available that inhibit the reF~ qtinl~ of human ;~ o~icr~:G~c~ viruscs in T cells and lno~ocyt~,s (Y~u.,ho&~ et aL?
10 ~an~ (1986);1:575-580 and Broder et al., L,ancet (1985); ~:627-630). These c~ ds are limited in their usefulness duc to signifi~nt toYi~itieS and viral ,e ~c~i~t~ with their long-terrn use Volberding, et al., N. F~Fl J. Med 1990; 322:941-949. ~ tionqlly~ ccrtain select d o~ y~s~ tory agents have ~ t._d an ability to 5 sl~yp~ss ~ fi~;Qn SPC~ A11Y~ n~ tinS~ CD8 Iymphocytes have been shown to ~Uyyl~ s l~l;.-nl;Qn of HIV in ~iyhc~l blood ~ o~ le~r cells (WaL~er et al. S~i~-n~ ~L:1563-6 (1986~) and achvated CD8+ T cells have bccn shown to inhibit the rcpliC~ti~ n of HIV in cultures of CD4+ cells from asy~tom tic HIV sc,v~ e individuals (n~ -Anl~ ct al. CD8+ T cells L
~ .. ,.. 1 1442961-2966(1990)). Further,the;.. ~ o~u~ssi~ecc.. l~.... A
c~r~lG~ A (CsA) has ~ att,d a p~t~li~e effect in several animal mf~d~lc of viral ;~r~;n~ P~~ , chronic l,c~ with C~sA before and aftcr il~rcclioA WitA LP-BM5 murinc 1~ virus has proven effcc~ve against thc d~,~clo~ t of ;~ no~1er~ncy disease (Cerny, A. ct al. P.llr J. I.. -- l ~:1747-50 (1991)). Evidence that l~ c-~ of AIDS and HIV-se,~.~osili~e non-AIDS y~;r~ with CsA i,.c,~ases T4 cells and inhibits lyll~yknA~ l~a~ has also been ~pOlt~. (Andrieu et al. C:lin. I.. ~n~ n~ l.. n~patl~ol. 46:181-198 (1988)). II~ ., none of thc above icrc.~ ces suggest that osL~yyl~s~ u~n~ul~toT~ agcnts in gcncral will havc utility in 30 inh;bit;ng thc y~ c~;OI~ of i--fcr~:ous HIV in HIV sc,opos;li~re h~ 5, Further, none of the above l.,f~ nces teaches or suggest a means for ~ I,cll.e. a particular ;~ no~ ~py~s~ c....od~ tnry agent will have utility in int~ihitin~ the ylu~CI;Q~ of inf~ous HIV in HIV s~ e h~ n~
Badgcr, ct al., U.S. Patent No. 4,963,~7 (Badger I) discloses co~,lyounds 35 of the f~m~
21 6~784 ~
R~((CH2)m 1 \ (CH2) --4 (I) wherein: 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 com~ined by R1 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 ~lirrcl~;nt and are selected 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 hct.,n,cyclic group having 5-8 atoms; or a pharrn~ceutic~lly acceptable salt or hydrate or solvate thereof.
Badger I discloses compounds of Formula I as a class of novel compounds which induce an i~ olllodul~tory effect which is characterized by the stim~ tion of ~,u~)pl~,ssor cell activity.
Badger I does not disclose the colnyoullds of Forrnula I as agents for inhib;ting the production of infectious HIV in HIV seropositive humans.
Sulnl~ of the Invention This invention relates to a method of inhibiting the production of infectious HIV in HIV seropositive hum~nc which comprises ~mini~tering to such human an effective amount of a comyound of the formula R~O((CH2)m 1 \ (CH2)n ~ \
4 (I) whe.e;n:
nis3-7;
m is 1 or 2;
R1 and R2 are the same or different and are selected from hydrogen or 25 straight or branched chain alkyl, provided that the total number of carbon atoms con~ ed by R1 and R2 when taken together is 5-10; or Rl 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 30 with the nitrogen atom to form a heterocyclic group having 5-8 atoms;
VIRUSES WITH SUBSTITUTED AZASPIRANES
This invention relates to a method of inhibiting the protl.~ction Of il~rcc!io~ human ;~l~ln~ ~erlriency viruses (HIV) in HIV s~,.u~,o~ /e hnm~n~
which comprises r ~minicterin~ to such human an effective amount of a su~
5 ~?~U~C.
R~rL ~.o.~ntl of the Inverltion Nu~ wuus agents are yl~;s~ ~tly available that inhibit the reF~ qtinl~ of human ;~ o~icr~:G~c~ viruscs in T cells and lno~ocyt~,s (Y~u.,ho&~ et aL?
10 ~an~ (1986);1:575-580 and Broder et al., L,ancet (1985); ~:627-630). These c~ ds are limited in their usefulness duc to signifi~nt toYi~itieS and viral ,e ~c~i~t~ with their long-terrn use Volberding, et al., N. F~Fl J. Med 1990; 322:941-949. ~ tionqlly~ ccrtain select d o~ y~s~ tory agents have ~ t._d an ability to 5 sl~yp~ss ~ fi~;Qn SPC~ A11Y~ n~ tinS~ CD8 Iymphocytes have been shown to ~Uyyl~ s l~l;.-nl;Qn of HIV in ~iyhc~l blood ~ o~ le~r cells (WaL~er et al. S~i~-n~ ~L:1563-6 (1986~) and achvated CD8+ T cells have bccn shown to inhibit the rcpliC~ti~ n of HIV in cultures of CD4+ cells from asy~tom tic HIV sc,v~ e individuals (n~ -Anl~ ct al. CD8+ T cells L
~ .. ,.. 1 1442961-2966(1990)). Further,the;.. ~ o~u~ssi~ecc.. l~.... A
c~r~lG~ A (CsA) has ~ att,d a p~t~li~e effect in several animal mf~d~lc of viral ;~r~;n~ P~~ , chronic l,c~ with C~sA before and aftcr il~rcclioA WitA LP-BM5 murinc 1~ virus has proven effcc~ve against thc d~,~clo~ t of ;~ no~1er~ncy disease (Cerny, A. ct al. P.llr J. I.. -- l ~:1747-50 (1991)). Evidence that l~ c-~ of AIDS and HIV-se,~.~osili~e non-AIDS y~;r~ with CsA i,.c,~ases T4 cells and inhibits lyll~yknA~ l~a~ has also been ~pOlt~. (Andrieu et al. C:lin. I.. ~n~ n~ l.. n~patl~ol. 46:181-198 (1988)). II~ ., none of thc above icrc.~ ces suggest that osL~yyl~s~ u~n~ul~toT~ agcnts in gcncral will havc utility in 30 inh;bit;ng thc y~ c~;OI~ of i--fcr~:ous HIV in HIV sc,opos;li~re h~ 5, Further, none of the above l.,f~ nces teaches or suggest a means for ~ I,cll.e. a particular ;~ no~ ~py~s~ c....od~ tnry agent will have utility in int~ihitin~ the ylu~CI;Q~ of inf~ous HIV in HIV s~ e h~ n~
Badgcr, ct al., U.S. Patent No. 4,963,~7 (Badger I) discloses co~,lyounds 35 of the f~m~
21 6~784 ~
R~((CH2)m 1 \ (CH2) --4 (I) wherein: 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 com~ined by R1 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 ~lirrcl~;nt and are selected 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 hct.,n,cyclic group having 5-8 atoms; or a pharrn~ceutic~lly acceptable salt or hydrate or solvate thereof.
Badger I discloses compounds of Formula I as a class of novel compounds which induce an i~ olllodul~tory effect which is characterized by the stim~ tion of ~,u~)pl~,ssor cell activity.
Badger I does not disclose the colnyoullds of Forrnula I as agents for inhib;ting the production of infectious HIV in HIV seropositive humans.
Sulnl~ of the Invention This invention relates to a method of inhibiting the production of infectious HIV in HIV seropositive hum~nc which comprises ~mini~tering to such human an effective amount of a comyound of the formula R~O((CH2)m 1 \ (CH2)n ~ \
4 (I) whe.e;n:
nis3-7;
m is 1 or 2;
R1 and R2 are the same or different and are selected from hydrogen or 25 straight or branched chain alkyl, provided that the total number of carbon atoms con~ ed by R1 and R2 when taken together is 5-10; or Rl 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 30 with the nitrogen atom to form a heterocyclic group having 5-8 atoms;
7vo 95/03W1 2 1 6 7 8 4 1 PcT/uss4/0827s or a pharmaceutically acceptable salt or hydrate or solvate thereof.
Detailed Description of the Invention The prep~a~ion of all compounds of Forrnula (I) and pharm~ceutic~11y 5 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 inco,l,~,lated by ,~r~c~.
A ~l~;f~ ,d co,l~pou~1~1 used in the novel method is the dihydrochloride salt of a compound of Formula (I) where Rl and R2 are propyl, R3 and R4 are methyl, lO m is l and n is 3 which is N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-p~p~ . I l i ne dihydrochloride.
A particularly lulGrGIl~d compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R l and R2 are propyl, R3 and R4 are ethyl, m is l and n is 3 which is N,N-diethyl-8,8-dipropyl-2-l5 azaspiro[4.s]decane-2-prop~n~mine dihydrochloride.
A particularly plGÇGll~id co.,.pound used in the novel method is the dihydrochloride salt of a co"")ound of Formula (I) where R 1 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 dihydrochloride-This invention ~ closes co"")ounds of Formula (I) and pharm~euti~11y~cept~hle salts or hydrates or solvates thereof as being useful for inhibiting the production of infectious HIV in HIV seç~osi~i~e humans.
The collll-ounds of Formula I are tested for their ability to inhibit the 25 ~,~luc!;on of infectious HIV in the assay described in Sperber, et al., Research and Human Retroviruses. 2 No.l, 9l-98.
This invention relates to a method of inhibiting the production of infectious HIV which compri~es ~rlmini~tPring to an HIV seropositive human an ~rr~c,i~e amount of a co"-~,ou"d of Formula (I) or a pharm~cel1tic~11y ~ccept~hle 30 salt or hydrate or solvate thereof. A compound of Formula (I) or a pha.l..~r~u~ 11y ~ccept~hle salt or hydrate or solvate thereof can be ~dmini~tered to such human in a conventional dosage form prepared by combining a co",l)ound of Formula (I) or a pharm~seutic~l1y acceptable salt or hydrate or solvate thereof, with a conventional pharm~ceuti~lly acceptable 35 carrier or diluent according to known techniques, such as those described in Badger (I), U.S. Patent No. 4,963,557.
Wo 95/0304l 2 1 6 7 8 4 1 PCT/USg4/08275 It will be recognized by one of skill in the art that the form and character of the ph~..~ c..lic~lly acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of ~A~lminictration and other well-known variables. A compound of Formula (I) or a pharm~ce11tir~11y 5 acceptable salt or hydrate or solvate thereof is ~rlminictered to an HIV
seropositive human in an amount sufficient to inhibit the production of infectious HIV
The route of ~tlminictration of the Formula (I) ("active ingredient") co~ uu,.d is not critical but is usually oral or parenteral, preferably oral.
The term ~lent~,.dl as used herein includes intravenous, intram-1cc~ r, subcut~neouc, intranasal, i~lLralc~,lal, transdermal, intravaginal or in~,~eliloneal minic~ration. The subcu~aneous and intramuscular forms of parenteral ~rlminic~ration are generally ~,lefe"cd. The daily parenteral dosage regimen will preferably be from about O.Ol mg/kg to about lO mg/kg of total body weight, most preferably from about O.l mg/kg to about l mg/kg. Preferably, each ,a,Gnte.~l dosage unit will contain the active ingredient in an amount of from about 0.1 mg to about lO0 mg.
The co~ oullds of Formula (I) which are active when given orally can be f~ t~d as liquids, for eY~mrle syrups, s11cpçnsions or çm111cionc tablets, c~rs111es and 107enges A liquid formulation will generally consist of a suspension or solution of the colll~lnd or ph~ e.,'i~a11y acceptable salt in a suitable liquid carrier(s) for eY~rnple~ eth~no1, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a ~cl~e.lll;ng agent, preservative, flavoring or coloring agent.
A comrosition in the form of a tablet can be p~)~ed using any suitable ph~.lll~c~l;c~1 carrier(s) routinely used for p,et)a,ing solid fo~n111~tionc Examples of such ca~iers include m~ esilllll stearate, starch, lactose, sucrose and cellulose.
A co~ o~;l ;on in the fo~n of a capsule can be p~p~,d using routine e~Aps.l1~tion ~,ocedurGs. For example, pellets cont~ining the active ingl~.iient can be plep~ed using standard carriers and then filled into a hard gelatin c~ps1.1t~,;
alternatively, a dispersion or sUcpension can be ~lGpal~d using any suitable ph~ll~ 1 carrier(s), for ~x~mrle aqueous gums, celluloses, silicates or oils and the dispersion or s~cl e~l~;on then filled into a soft gelatin capsule.
The daily oral dosage legi-llen will preferably be from about O.Ol mg/lcg 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 O.l mg to about lO0 mg.
wo 95~03041 2 1 6 7 8 4 1 PCT/US94/08275 While it is possible for an active ingredient to be ~minictered 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 (I) or a 5 pharm~ceutic~lly 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 arlminictration, and the particular patient being treated, and that such ollt~lums can be ~ct~ l.l;neA by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatm~nt~ i.e., 10 the r,ulll~. of doses of a collll,o--nd of Formula (I) or a pharmaceutically açcept~ble salt or hydrate or solvate thereof given per day and duration of therapy, can be ascertained by those skilled in the art using conventional course of treatment determin~tion tests.
The method of this invention of inhibiting the production of infectious HIV
15 in HIV seropositive humans comprises ~tlminictering to a subject in need of such inhibition an effective infectious HIV inhibiting amount of a pharm~re~ltic~lly active cc,l-.pound of the present invention.
The invention also provides for the use of a coll-pouild of Formula (I) in the m~nufa~tnre of a meAir~m--nt for use in the inhibition of infectious HIV in HIV
20 se.l~osili~/e hl~m~n~
The invention also provides for a ph~...~reuti~l composition for use in the inhibjtiQn of the production of infectious HIV in HIV seropositive hl~m~nc whichcomprises a coll-~ound of Formula I and a pharm~ceutiG~lly acceptable carrier.
The invention also provides for a process for preparing a pharm~ceutir~l 25 col os;l;on cor.~ g a pha~ celll;r~lly acceptable carrier or diluent and a coll.~ound of Formula I which comprises bringing the compound of Formula I into ~C~oci~tion with the ph~rm~reutir~lly acceptable carrier or diluent.
No un~rcept~ble to~icological effects are e~l)ecled when cGmpounds of the invention are ~lminictçred in accordance with the present invention.
In addition, the compounds of the present invention can be co-~lministçred with further active ingre~ient~ such as compounds known to prevent or delay the occul.~,nce of AIDS in HIV seropositive humans such as retrovir (the brand name for zidovudine, fc,~ elly called azidothymidine (AZT)).
Without further elaboration, it is believed that one skilled in the art can, using the preceding descli~on, utilize the present invention to its fullest extent.
The following examples are, thclefolG, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.
An oral dosage form for ~Amini~tering Formula (I) compounds is produced by filing a standard two piece hard gelatin capsule with the ingredients in the plulJullions shown in Table I, below.
Table I
INGREDlFNTS AMOUN~S
N,N-diethyl-8,8-dipropyl-2-a2aspiro[4,5]decane-2- 25 mg p~ns...~ e dihydrochloride ~ ~ctose 55 mg Talc 16 mg Magnesium Stearate 4 mg EXAMPLE 2 - INJECTABl F PARENTERAL COMPOSITION
An injectable form for ~Clministering Formula (I) compounds is produced by stirring 1.5% by weight of N,N-diethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2-prop~n~mine dihydrochloride in 10% by volume propylene glycol in water.
F.x~ml?le 3 - Tablet Composition The sucrose, c~l~ium sulfate dihydrate and Formula (I) coml,ound shown in 15 Table II below, are mixed and granulated in the ~lopolLions shown with a 10%
gelatin solution The wet granules are s~l~ened, dried, mixed with the starch, talc and stearic acid, scree,lcd and cûlll~l~,ssed into a tablet.
Table II
In~redients Amounts N,N-diethyl-8,8-dipropyl-2-~s~ [4,5]decane- 20 mg 2-plU~ dihydroc~hl-)riCle cal~ m sulfate dihydrate 30 mg sucrose 4 mg starch 2 mg talc 1 mg stearic acid 0.5 mg While the above des~ ions and examples fully describe the invention and the pl~f~ d embo~ .c~ thereof, it is understood that the invention is not limited tû the particular disclosed embodhllents coming within the scope of the following claims.
Detailed Description of the Invention The prep~a~ion of all compounds of Forrnula (I) and pharm~ceutic~11y 5 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 inco,l,~,lated by ,~r~c~.
A ~l~;f~ ,d co,l~pou~1~1 used in the novel method is the dihydrochloride salt of a compound of Formula (I) where Rl and R2 are propyl, R3 and R4 are methyl, lO m is l and n is 3 which is N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-p~p~ . I l i ne dihydrochloride.
A particularly lulGrGIl~d compound used in the novel method is the dihydrochloride salt of a compound of Formula (I) where R l and R2 are propyl, R3 and R4 are ethyl, m is l and n is 3 which is N,N-diethyl-8,8-dipropyl-2-l5 azaspiro[4.s]decane-2-prop~n~mine dihydrochloride.
A particularly plGÇGll~id co.,.pound used in the novel method is the dihydrochloride salt of a co"")ound of Formula (I) where R 1 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 dihydrochloride-This invention ~ closes co"")ounds of Formula (I) and pharm~euti~11y~cept~hle salts or hydrates or solvates thereof as being useful for inhibiting the production of infectious HIV in HIV seç~osi~i~e humans.
The collll-ounds of Formula I are tested for their ability to inhibit the 25 ~,~luc!;on of infectious HIV in the assay described in Sperber, et al., Research and Human Retroviruses. 2 No.l, 9l-98.
This invention relates to a method of inhibiting the production of infectious HIV which compri~es ~rlmini~tPring to an HIV seropositive human an ~rr~c,i~e amount of a co"-~,ou"d of Formula (I) or a pharm~cel1tic~11y ~ccept~hle 30 salt or hydrate or solvate thereof. A compound of Formula (I) or a pha.l..~r~u~ 11y ~ccept~hle salt or hydrate or solvate thereof can be ~dmini~tered to such human in a conventional dosage form prepared by combining a co",l)ound of Formula (I) or a pharm~seutic~l1y acceptable salt or hydrate or solvate thereof, with a conventional pharm~ceuti~lly acceptable 35 carrier or diluent according to known techniques, such as those described in Badger (I), U.S. Patent No. 4,963,557.
Wo 95/0304l 2 1 6 7 8 4 1 PCT/USg4/08275 It will be recognized by one of skill in the art that the form and character of the ph~..~ c..lic~lly acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of ~A~lminictration and other well-known variables. A compound of Formula (I) or a pharm~ce11tir~11y 5 acceptable salt or hydrate or solvate thereof is ~rlminictered to an HIV
seropositive human in an amount sufficient to inhibit the production of infectious HIV
The route of ~tlminictration of the Formula (I) ("active ingredient") co~ uu,.d is not critical but is usually oral or parenteral, preferably oral.
The term ~lent~,.dl as used herein includes intravenous, intram-1cc~ r, subcut~neouc, intranasal, i~lLralc~,lal, transdermal, intravaginal or in~,~eliloneal minic~ration. The subcu~aneous and intramuscular forms of parenteral ~rlminic~ration are generally ~,lefe"cd. The daily parenteral dosage regimen will preferably be from about O.Ol mg/kg to about lO mg/kg of total body weight, most preferably from about O.l mg/kg to about l mg/kg. Preferably, each ,a,Gnte.~l dosage unit will contain the active ingredient in an amount of from about 0.1 mg to about lO0 mg.
The co~ oullds of Formula (I) which are active when given orally can be f~ t~d as liquids, for eY~mrle syrups, s11cpçnsions or çm111cionc tablets, c~rs111es and 107enges A liquid formulation will generally consist of a suspension or solution of the colll~lnd or ph~ e.,'i~a11y acceptable salt in a suitable liquid carrier(s) for eY~rnple~ eth~no1, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a ~cl~e.lll;ng agent, preservative, flavoring or coloring agent.
A comrosition in the form of a tablet can be p~)~ed using any suitable ph~.lll~c~l;c~1 carrier(s) routinely used for p,et)a,ing solid fo~n111~tionc Examples of such ca~iers include m~ esilllll stearate, starch, lactose, sucrose and cellulose.
A co~ o~;l ;on in the fo~n of a capsule can be p~p~,d using routine e~Aps.l1~tion ~,ocedurGs. For example, pellets cont~ining the active ingl~.iient can be plep~ed using standard carriers and then filled into a hard gelatin c~ps1.1t~,;
alternatively, a dispersion or sUcpension can be ~lGpal~d using any suitable ph~ll~ 1 carrier(s), for ~x~mrle aqueous gums, celluloses, silicates or oils and the dispersion or s~cl e~l~;on then filled into a soft gelatin capsule.
The daily oral dosage legi-llen will preferably be from about O.Ol mg/lcg 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 O.l mg to about lO0 mg.
wo 95~03041 2 1 6 7 8 4 1 PCT/US94/08275 While it is possible for an active ingredient to be ~minictered 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 (I) or a 5 pharm~ceutic~lly 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 arlminictration, and the particular patient being treated, and that such ollt~lums can be ~ct~ l.l;neA by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatm~nt~ i.e., 10 the r,ulll~. of doses of a collll,o--nd of Formula (I) or a pharmaceutically açcept~ble salt or hydrate or solvate thereof given per day and duration of therapy, can be ascertained by those skilled in the art using conventional course of treatment determin~tion tests.
The method of this invention of inhibiting the production of infectious HIV
15 in HIV seropositive humans comprises ~tlminictering to a subject in need of such inhibition an effective infectious HIV inhibiting amount of a pharm~re~ltic~lly active cc,l-.pound of the present invention.
The invention also provides for the use of a coll-pouild of Formula (I) in the m~nufa~tnre of a meAir~m--nt for use in the inhibition of infectious HIV in HIV
20 se.l~osili~/e hl~m~n~
The invention also provides for a ph~...~reuti~l composition for use in the inhibjtiQn of the production of infectious HIV in HIV seropositive hl~m~nc whichcomprises a coll-~ound of Formula I and a pharm~ceutiG~lly acceptable carrier.
The invention also provides for a process for preparing a pharm~ceutir~l 25 col os;l;on cor.~ g a pha~ celll;r~lly acceptable carrier or diluent and a coll.~ound of Formula I which comprises bringing the compound of Formula I into ~C~oci~tion with the ph~rm~reutir~lly acceptable carrier or diluent.
No un~rcept~ble to~icological effects are e~l)ecled when cGmpounds of the invention are ~lminictçred in accordance with the present invention.
In addition, the compounds of the present invention can be co-~lministçred with further active ingre~ient~ such as compounds known to prevent or delay the occul.~,nce of AIDS in HIV seropositive humans such as retrovir (the brand name for zidovudine, fc,~ elly called azidothymidine (AZT)).
Without further elaboration, it is believed that one skilled in the art can, using the preceding descli~on, utilize the present invention to its fullest extent.
The following examples are, thclefolG, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.
An oral dosage form for ~Amini~tering Formula (I) compounds is produced by filing a standard two piece hard gelatin capsule with the ingredients in the plulJullions shown in Table I, below.
Table I
INGREDlFNTS AMOUN~S
N,N-diethyl-8,8-dipropyl-2-a2aspiro[4,5]decane-2- 25 mg p~ns...~ e dihydrochloride ~ ~ctose 55 mg Talc 16 mg Magnesium Stearate 4 mg EXAMPLE 2 - INJECTABl F PARENTERAL COMPOSITION
An injectable form for ~Clministering Formula (I) compounds is produced by stirring 1.5% by weight of N,N-diethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2-prop~n~mine dihydrochloride in 10% by volume propylene glycol in water.
F.x~ml?le 3 - Tablet Composition The sucrose, c~l~ium sulfate dihydrate and Formula (I) coml,ound shown in 15 Table II below, are mixed and granulated in the ~lopolLions shown with a 10%
gelatin solution The wet granules are s~l~ened, dried, mixed with the starch, talc and stearic acid, scree,lcd and cûlll~l~,ssed into a tablet.
Table II
In~redients Amounts N,N-diethyl-8,8-dipropyl-2-~s~ [4,5]decane- 20 mg 2-plU~ dihydroc~hl-)riCle cal~ m sulfate dihydrate 30 mg sucrose 4 mg starch 2 mg talc 1 mg stearic acid 0.5 mg While the above des~ ions and examples fully describe the invention and the pl~f~ d embo~ .c~ thereof, it is understood that the invention is not limited tû the particular disclosed embodhllents coming within the scope of the following claims.
Claims (6)
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 production of infectious human immunodeficiency viruses (HIV) in HIV seropositive humans.
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 production of infectious 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.
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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9315306.2 | 1993-07-23 | ||
| GB939315306A GB9315306D0 (en) | 1993-07-23 | 1993-07-23 | Methods |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2167841A1 true CA2167841A1 (en) | 1995-02-02 |
Family
ID=10739328
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002167841A Abandoned CA2167841A1 (en) | 1993-07-23 | 1994-07-22 | Method of inhibiting the production of human immunodeficiency viruses with substituted azaspiranes |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0713391A4 (en) |
| CN (1) | CN1130870A (en) |
| AU (1) | AU7370894A (en) |
| CA (1) | CA2167841A1 (en) |
| GB (1) | GB9315306D0 (en) |
| NZ (1) | NZ269990A (en) |
| WO (1) | WO1995003041A1 (en) |
| ZA (1) | ZA945416B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9315340D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
| GB9315351D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
| BR9601909A (en) * | 1995-07-13 | 1999-10-13 | Smithkline Beecham Corp | N, n-diethyl-8,8-dipropyl-2-azaspiro (4,5) decane-2-propan amine dimaleate |
| WO1997044030A1 (en) * | 1996-05-17 | 1997-11-27 | Anormed Inc. | Use of substituted azaspirane in the treatment of asthma |
| TW574036B (en) | 1998-09-11 | 2004-02-01 | Elan Pharm Inc | Stable liquid compositions of botulinum toxin |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4963557A (en) * | 1987-09-28 | 1990-10-16 | Smithkline Beecham Corporation | Immunomodulatory azaspiranes |
| ZA921120B (en) * | 1991-02-19 | 1993-01-27 | Smithkline Beecham Corp | Cytokine inhibitors |
| GB9201803D0 (en) * | 1992-01-28 | 1992-03-11 | Smithkline Beecham Corp | Methods |
| GB9201804D0 (en) * | 1992-01-28 | 1992-03-11 | Smithkline Beecham Corp | Methods |
| GB9315340D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
| GB9315351D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
| GB9315271D0 (en) * | 1993-07-23 | 1993-09-08 | Smithkline Beecham Corp | Methods |
-
1993
- 1993-07-23 GB GB939315306A patent/GB9315306D0/en active Pending
-
1994
- 1994-07-22 NZ NZ269990A patent/NZ269990A/en unknown
- 1994-07-22 CN CN94193372A patent/CN1130870A/en active Pending
- 1994-07-22 EP EP94922684A patent/EP0713391A4/en not_active Withdrawn
- 1994-07-22 AU AU73708/94A patent/AU7370894A/en not_active Abandoned
- 1994-07-22 ZA ZA945416A patent/ZA945416B/en unknown
- 1994-07-22 WO PCT/US1994/008275 patent/WO1995003041A1/en not_active Application Discontinuation
- 1994-07-22 CA CA002167841A patent/CA2167841A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| GB9315306D0 (en) | 1993-09-08 |
| AU7370894A (en) | 1995-02-20 |
| NZ269990A (en) | 1999-07-29 |
| CN1130870A (en) | 1996-09-11 |
| WO1995003041A1 (en) | 1995-02-02 |
| EP0713391A1 (en) | 1996-05-29 |
| ZA945416B (en) | 1995-05-10 |
| EP0713391A4 (en) | 1998-09-09 |
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