Note: Descriptions are shown in the official language in which they were submitted.
~0~3/14760 2~2~3 ~ P~T/U~93/~730
~,
-- 1 --
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~. This invention relates to a method of preventing
or delaying the occurrence of acquired immunodeficiency
syndrome tAIDS) in human im~un~de~icien~y ~irus ~HIV)
seropositi~e humans which comprises administering to:
such human an effective therefore amount of a
substituted azaspirane.
0 ~ :
k~r~ J2~ LI~n~inn
The use of immunosuppressive~immunomodulatory
a~ents has been ~hown ~o suppres~s viral rep~ication.
Specifically~ lmmunomodulating~CD8 lympho~cytes have
~S been shown to supprèss replication of HIV iD peripheral
blood mo~onuclear cells~(Waler ~t al. ~ ~ ~
23~:1563-6: (1986)j~and activated CD8* T cells~have been:
~: show~ to inhibit the replication of HIV in culturès~ of~
CD4+ celIs from asymptomatic HIV seropos}tlve
indiv~duals (Brinchm~nn et al. CD8+ T cells ~L~ &a
2961 2966 (l990)). Further, the immunosuppressive
; compound cyclo5porin A (CsA) has demonstrated a
protective effect in several animal models of viral : :
infectionO Particularly, chronic treatment~with CsA
h~ore and after infection with LP~BMS murine leukemia
virus has proven e~fective ayainst the development of
imlhunodeficiency diseas~ (Cerny, A. et al. ~.I.
Imm~n~l~ 21:1747-50 (19gl) ~ . Evidence that tr~atment
W093/14760 2~ ~ i3 i _ 2 - PCT/US~3/0073
of AIDS and HIV-seropositive non-AIDS patients with CsA
increases T4 cells and inhibits lymphadenopathy has
also been reported. (Andrieu et al. Clin. Imm~nol~_and
~:181~198 (1988)).
Badger, et al., U.S. Patent No. 4,963,557
(B2dger I) discloses compounds of the formula
R \--/ ( 2)m ~ (~H2)~
4 (I)
wherein: n is 3-7; m is 1 or 2; Rl and R2 axe the same
or different and axe selected from hydrogen or straight
or branched chain alkyl, provided that the total number
of carbon atGms contained by R1 and R2 when taken
together is 5-10; or R1 and R~ 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 jolned together with the ni~rogen atom to form a
heterocyclic ~roup ha~ing 5~8 atoms; or a
pharmaceutically acceptable salt or hydrate or solvate
thereof.
. Badyer I discloses compounds of Formula I as a
novel class of compounds which induce an
immunomodulatory ef~ect which is characterized by the
stimulation of suppressor cell activity.
Badgex I does not disclose the compounds of Formula
I as agents for preventing or delaying the occurrence of
AIDS in HIV seropositive humans.
~093~14760 ~1 2 8 ~ 3 `~ P~T/US93/0073
-- 3
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
5 effective therefor amount of a compound of the formula
R2 ~ ~ \ (CH )--N /
R4 (I)
wherein:
lO ~ n is 3-7;
m is l or 2;
Rl and R2 are the same o:r different and are
selected from hydrogen or str,~ight or branched chain
alkyl, provided that the total number of carbon atoms
15 contained by Rl and R2 when taken together is 5-lO; 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
20 l 3 carbon atoms; or R3 and R4 arè joined together wi~h
the nitrvgen atom t~ form a heterocyclic qroup having
5-8 atoms;
or a p~armaceutically acceptable salt or hydrate or
sol~ate thereof.
The preparation of all compounds of Formula ~I)
and pharmaceu~ically acceptable salts, hydrates and
solvates and formulations thereof is disclosed in U.S.
3Q Patent No. 4,963,557, the entire disclo5ure of which ls
hereby incorpor~ted by reference.
A preferred compound used in the novel method is
the dihydro~hloride salt of a compound of Formula (I)
wo93J14760 ~ PCT/~S93/00730
_ q
where R1 and R2 are propyl~ R3 and R4 are methyl, m is
1 and n is 3 which is N,N-dimethyl-8,8 dipropyl-2-
a~aspiro[4,5~decane-2-propanamine dihydrochloride.
A preferred compound used in the novel method is a
compound of Formula ~I~ where R1 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-azaspiro[4~53decane-2
propanamine 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
e~fective therefor amount of a compound of Formula (I)
or a pharmaceutically acceptable salt or hydrate or
sol~ate thereof. ~ compou~d of Formula (I~ ox a
pharmaceutically acceptable salt or hydrate or solvate
thereof can ~e administered to such human in a
~5 conventional dosage form prepared by combining a
compound of Formula (I) or a pharmaceutically
acceptable salt or hydrate or solvate thereof, with a
conventional pharmaceutically acceptable carrier or
diluent accordin~ to known 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 pharmaceutically
acceptable carrier or diluent is dictated by the
amount of active in~redient with which it is to be
combined, the route of administration and other well-
known variables. A compou~d of Formula ~I) or a
WO93/14760 ~1 2~ i3cj PC~/US93/00730
.
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, su~cutaneous, intranasal,
intrarectal, transdermal, intravaginal or
intraperitoneal administrat~on. The subcutane~us and
intramuscular forms cf parenteral administration are
generally preferred. The daily parenteral dosage
regimen will preferably be from a}: out O . 01 mg/kg to
about 10 mg/kg of total body weight~ most preferably
from abou~ 0.1 mg/kg to àbout 1 mg/kg. Prefe~ably,
each parenteral dosage unit will contain the active
ingredient in an amount of from about 0.1 mg to about
100 ir.g.
The compounds of Formula (I) which are active when
gi~en 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 accepta~le salt in a suitable liquid
carrier(s~ for example, ethanol, ~lycerine, non~aqueous
solvent, for example polyethylene gIycol, 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)
W~ 93~14760 ~ ~ r PCI'/US93/00730
~J t ~ 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 proceduresO For
example, pellet~ 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 reg:imen will preferably be
from about 0,01 mg/kg to abo~t 10 mgfk~ 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 mg.
While it is possible for an actlve 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 (I) or a
pharmaceutirally acceptable salt or hydrate or solvate
thereof will be determined by the nature and extent o~
the condition being treated, the form, route and site
of administration, and the particular patient being
treatedr and that such optimums can be determined by
conventional techni~ues. It will also be appreciated
by one of skill in the art that the optimal course of
treatment, i.e., the number of doses of ~ compound of
Formula ~I) or a pharmaceutically acceptable salt or
hydrate or solvate thereof given per day and duration
wo ~3/~4760 2 ~. 2 8 ~i ? A''~ ~CT/~S~3J~730
, . . .
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
occurxence of AIDS in HIV seropositive humans such as
retrovir ~the brand name for zidovudine, formerly called
aæidothymidine (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.
An oral dosage form for administering Formula (I)
compounds is produced by ~iling a standard two piece
hard gelatin capsule with the ingredients in the
: 25 proportions shown in Table I, below.
AMOI~;T~
N,N-dimethyl-8, 8-dipropyl-2- 25 mg
azaspiro [4, 5~ decane-2-propanamine
dihydrochloride
Lactose 55 mg
Talc 16 m~ ;
Magnesium Stearate 4 mg
~_~=~
W~93/t476~ PCT/U~93/0~730
~ ~9 3 - 8 -
An injectable form for administering Formula (I)
compounds is produced b~ stirring 1.5% by weight of
N,N-dimethyl-8,8-dipropyl 2-azaspiro[9,5]decane~2-
propanamine dihydrochloride in 10% by volume propylene
glycol in water.
The sucrose, calcium sulfate dihydrate and Form~la
(I) 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.
N,N-diethyl-8,8-dipropyl--2- 20 mg:
a~aspiro[4,5]decan2-2-prc3panamine
: dihydrochloride
calcium sulfate dihydrate 30 mg
sucrose 4 mg
starch 2 m~
talc 1 mg
stearic acid 0.5 mg
While the above dessriptions and examples fully
describe the invention and the preferred embodiments
thereof, it is understood that the in~ention is not
limite~ to the particular disclosed embodiments coming
wi~hin the scope of the following claims.
