SI9400354A

SI9400354A - Pharmaceuticals compositions containing azaspirantic derivate.

Info

Publication number: SI9400354A
Application number: SI9400354A
Authority: SI
Inventors: Mary Alison Badger
Original assignee: Smithkline Beecham Corp
Priority date: 1994-09-13
Filing date: 1994-09-13
Publication date: 1996-04-30

Abstract

Prikazan je postopek za zdravljenje hiperlipidemije pri sesalcu, vključno človeku, ki to potrebuje, ki obega dajanje le-temu efektivno količinsko azaspiranskega derivata. Prikazani so tudi farmacevtski sestavki, ki vsebujejo azaspiranski derivat.A process for treating hyperlipidemia is presented in a mammal, including a human in need, who both administer to them effectively quantitatively azaspiranic derivatives. Pharmaceuticals are also shown compositions containing the azaspiranic derivative.

Description

SMITHKLINE BEECHAM CORPORATIONSMITHKLINE BEECHAM CORPORATION

Farmacevtski sestavki, ki vsebujejo azaspiranski derivatPharmaceutical compositions containing the azaspiranic derivative

Predloženi izum se nanaša na postopek za zdravljenje hiperlipidemije pri sesalcu, vključno človeku, ki to potrebuje, ki obsega dajanja le-temu efektivno količino azaspiranskega derivata.The present invention relates to a method for treating hyperlipidemia in a mammal, including a human in need thereof, comprising administering to it a effective amount of an azaspiranic derivative.

Predloženi izum se nanaša tudi na farmacevtske sestavke, ki vsebujejo azaspiranski derivat.The present invention also relates to pharmaceutical compositions containing an azaspiranic derivative.

Badger et al., J. Med. Chem., 33, 2963-2970 (1990) opisujejo sorodnosti strukturne učinkovitosti azaspiranskih derivatov v testih za induciranje antiartritičnih in supresorskih celic. Navedena referenca prikazuje spojine, za katere so ugotovili, da so učinkovite in neučinkovite v testih v katerih so jih uporabili. Badger et al. so ugotovili, da spojina 2-[2-(dimetilamino)etil]-8,8-dipropil-2-azaspiro[4.5]dekan dihidroklorid nima biološko pomembne učinkovitosti.Badger et al., J. Med. Chem., 33, 2963-2970 (1990) describe related structural efficiencies of azaspiranine derivatives in anti-arthritic and suppressor cell induction assays. That reference shows the compounds found to be effective and ineffective in the tests in which they were used. Badger et al. found that compound 2- [2- (dimethylamino) ethyl] -8,8-dipropyl-2-azaspiro [4.5] decane dihydrochloride had no biologically significant efficacy.

Predloženi izum se nanaša na postopek za zdravljenje hiperlipidemije pri sesalcu, vključno človeku, ki to potrebuje, ki obsega dajanje le-temu učinkovito količino spojine s formulo IThe present invention relates to a method for treating hyperlipidemia in a mammal, including a human in need thereof, comprising administering to it an effective amount of a compound of formula I

kjer je n 1 ali 2;where n is 1 or 2;

R¹ in R² sta enaka ali različna in sta izbrana izmed vodika ali alkila z ravno ali razvejeno verigo ali cikličnega alkila, pod pogojem, da je celotno število atomov ogljika v R¹ in R², vzeto skupaj, od 0 do 10; ali sta R¹ in R² združena skupaj, da nastane ciklična alkilna skupina s 3 do 7 atomi ogljika; in sta R³ in R⁴ enaka ali različna in izbrana izmed vodika ali metila;R ¹ and R ² are the same or different and are selected from straight or branched chain hydrogen or alkyl or cyclic alkyl, provided that the total number of carbon atoms in R ¹ and R ² taken together is 0 to 10; or R ¹ and R ^{2 are} combined together to form a cyclic alkyl group of 3 to 7 carbon atoms; and R ³ and R ^{4 are the} same or different and selected from hydrogen or methyl;

ali njene farmacevtsko sprejemljive soli, hidrata ali solvata.or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Predloženi izum se nanaša tudi na farmacevtske sestavke, ki vsebujejo spojine s formulo I.The present invention also relates to pharmaceutical compositions containing compounds of formula I.

Z izrazom hiperlipidemija, kot ga uporabljamo v opisu prijave in v zahtevkih, je mišljeno, da so nivoji lipidov v krvi nenormalno visoki.The term hyperlipidemia, as used in the application description and in the claims, is meant to mean abnormally high blood lipid levels.

Izraz antihiperlipidemično, kot ga uporabljamo tukaj, pomeni znižanje prebitnih lipidnih koncentracij na želene nivoje.The term antihyperlipidemic, as used herein, means the reduction of excess lipid concentrations to the desired levels.

Prednostni lipidi, katerih visoke nivoje zdravimo s postopki v smislu izuma, so: holesterol, trigliceridi in lipoproteini z nizko gostoto.Preferred lipids whose high levels are treated by the methods of the invention are: cholesterol, triglycerides and low density lipoproteins.

Spojine s formulo I lahko pripravimo z znanimi postopki kot jih opisujejo Badger, et al. v J. Med. Chem., 33, 2963-2970, (1990) in v US patentu št. 4,963,557. Farmacevtsko sprejemljive soli, hidrate in solvate spojine s strukturo I tvorimo, če je potrebno, s postopki, dobro znanimi strokovnjakom.The compounds of formula I can be prepared by known methods as described by Badger, et al. in J. Med. Chem., 33, 2963-2970, (1990) and in U.S. Pat. No. 4,963,557. Pharmaceutically acceptable salts, hydrates and solvates of structure I compounds are formed, if necessary, by methods well known in the art.

Spojine v smislu izuma, ki so koristne pri zdravljenju hiperlipidemije in so vključene v farmacevtske sestavke v smislu izuma, so tiste s formulo IThe compounds of the invention that are useful in the treatment of hyperlipidemia and are included in the pharmaceutical compositions of the invention are those of formula I

kjer je n 1 ali 2;where n is 1 or 2;

R¹ in R² sta enaka ali različna in sta izbrana izmed vodika ali aikila z ravno ali razvejeno verigo ali cikličnega aikila, pod pogojem, daje celotno število atomov ogljika v R¹ in R², vzeto skupaj, od 0 do 10; ali sta R¹ in R² združena skupaj, da nastane ciklična alkilna skupina s 3 do 7 atomi ogljika; in sta R³ in R⁴ enaka ali različna in izbrana izmed vodika ali metila;R ¹ and R ² are the same or different and are selected from straight or branched chain hydrogen or alkyl or cyclic alkyl, provided that the total number of carbon atoms in R ¹ and R ² taken together is 0 to 10; or R ¹ and R ^{2 are} combined together to form a cyclic alkyl group of 3 to 7 carbon atoms; and R ³ and R ^{4 are the} same or different and selected from hydrogen or methyl;

ali njihove farmacevtsko sprejemljive soli, hidrati ali solvati.or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Prednostna med spojinami s formulo I je 2-[2-(dimetilamino)etil]-8,8-dipropil-2azaspiro[4.5]dekan.Preferred among the compounds of formula I is 2- [2- (dimethylamino) ethyl] -8,8-dipropyl-2azaspiro [4.5] decane.

Kot uporabljamo tukaj, se izraz 2-[2-(dimetilamino)etil]-8,8-dipropil-2azaspiro[4.5]dekan nanaša na spojino s strukturoAs used herein, the term 2- [2- (dimethylamino) ethyl] -8,8-dipropyl-2azaspiro [4.5] decane refers to a compound of structure

Prednostno je spojina 2-[2-(dimetilamino)etil]-8,8-dipropil-2-azaspiro[4.5]dekan, če jo uporabimo, kot je opisano tukaj, v obliki dihidrokloridne soli.Preferably, 2- [2- (dimethylamino) ethyl] -8,8-dipropyl-2-azaspiro [4.5] decane is used as described herein in the form of a dihydrochloride salt.

Ugotovili smo, da so spojine s formulo I in njihove farmacevtsko sprejemljive soli, hidrati in solvati koristne pri zdravljenju hiperlipidemije pri sesalcu, vključno človeku, ki to potrebuje.The compounds of formula I and their pharmaceutically acceptable salts, hydrates and solvates have been found to be useful in the treatment of hyperlipidemia in a mammal, including a human in need thereof.

2-[2-(dimetilamino)etil]-8,8-dipropil-2-azaspiro[4.5]dekan dihidroklorid (zatem spojina A) testiramo za njegovo in vivo zmogljivost pri zniževanju serumskega holesterola v normalno holesterolemičnih psih v dveh eksperimentih.2- [2- (dimethylamino) ethyl] -8,8-dipropyl-2-azaspiro [4.5] decane dihydrochloride (then compound A) was tested for its in vivo capacity in lowering serum cholesterol in normal cholesterolemic dogs in two experiments.

Za izvedbo eksperimenta I uporabimo skupno 3 samice čistokrvnih normalno holesterolemičnih psov beagle (Marshall Animal Farms, Inc., North Rose, New York). Psi tehtajo med 8 in 15 kg na začetku študija. Pse vzdržujemo ob vodi iz vodovoda, ki jim je dosegljiva ad libitum iz sistema za avtomatično dovajanje vode, in standardni laboratorijski pasji hrani chow (Pruina Laboratory Cainine Chow®). Tri pse razvrstimo v tri enote in doziramo enkrat na dan z 1,0 mg/kg spojine A. Nivo holesterola za vsakega psa določimo na dneve -21, -14, -7 in 0 pred doziranjem. Doziranje pričnemo na dan 0, potem ko določimo končni predobdelovalni nivo holesterola in nadaljujemo do dneva 28. Nivoje holesterola za vsakega psa določimo na dneve 7, 14, 21 in 28 med obdelovanjem. Pse nahranimo s približno 300 g pasje hrane chow vsaj 1-2 uri pred doziranjem. Pse stradamo približno 21 do 23 ur predno jim vzamemo krvne vzorce.A total of 3 purebred normal cholesterolemic beagle dogs (Marshall Animal Farms, Inc., North Rose, New York) were used to perform Experiment I. Dogs weigh between 8 and 15 kg at the beginning of their studies. Dogs are maintained by water from an aqueduct that can be accessed ad libitum from an automatic feed system and standard laboratory dog feeds are chow (Pruina Laboratory Cainine Chow®). Three dogs were classified into three units and dosed once daily with 1.0 mg / kg of Compound A. The cholesterol level for each dog was determined on days -21, -14, -7 and 0 before dosing. We start dosing on day 0 after determining the final cholesterol pre-treatment level and continue to day 28. We determine the cholesterol levels for each dog on days 7, 14, 21 and 28 during treatment. Feed the dog about 300 g of dog food chow for at least 1-2 hours before dosing. Dogs are killed approximately 21 to 23 hours before blood samples are taken.

Eksperiment II izvedemo po enakem postopku kot eksperiment I. V eksperimentu II razvrstimo 9 samic čistokrvnih normalno holesterolemičnih psov beagle v 3 skupine naslednje:Experiment II was performed according to the same procedure as Experiment I. In Experiment II, 9 purebred normal cholesterolemic beagle dogs were classified into 3 groups as follows:

Skupina 1 kontrola, doziramo oralno enkrat na dan samo nosilec.Group 1 control, only the oral dose is administered once a day to the vehicle.

Skupina 2 nizka doza, doziramo oralno enkrat na dan 1,0 mg/kg spojine A. Skupina 3 visoka doza, doziramo oralno enkrat na dan 3,0 mg/kg spojine A.Group 2 low dose, dosed orally once daily 1.0 mg / kg of compound A. Group 3 high dose, dosed orally once daily 3.0 mg / kg of compound A.

V eksperimentu II doziranje nadaljujemo do dneva 35. Nivo holesterola za vsakega psa določimo na dneve 7,14,21, 28 in 35 med obdelovanjem.In Experiment II, dosing was continued until day 35. The cholesterol level for each dog was determined on days 7,14,21, 28 and 35 during treatment.

Testno spojino damo v želatinsko kapsulo, kontrolni psi pa prejmejo prazno kapsulo. Nivoje serumskega holesterola v vzorcih krvi določimo na kemijskem analizatorju Instramentation Laboratories Monarch ob uporabi komercialnih reagentov od Instramentation Laboratories.The test compound is placed in a gelatin capsule and control dogs receive an empty capsule. Serum cholesterol levels in blood samples were determined on an Instramentation Laboratories Monarch chemical analyzer using commercial reagents from Instramentation Laboratories.

Pri obdelavi psov z 2-[2-(dimetilamino)etil]-8,8-dipropil-2-azaspiro[4.5]dekan dihidrokloridom pride do znatnega padca v nivojih serumskega holesterola. Torej je posledica dajanja 2-[2-(dimetilamino)etil]-8,8-dipropil-2-azaspiro[4.5]dekana terapevtsko znižanje nivojev serumskega holesterola pri sesalcih.Treatment of dogs with 2- [2- (dimethylamino) ethyl] -8,8-dipropyl-2-azaspiro [4.5] decane dihydrochloride results in a significant decrease in serum cholesterol levels. Thus, administration of 2- [2- (dimethylamino) ethyl] -8,8-dipropyl-2-azaspiro [4.5] Dean resulted in a therapeutic decrease in serum cholesterol levels in mammals.

Ker spojine s formulo I znižajo serumski holesterol, so terapevtsko koristne pri zdravljenju hiperlipidemije.Because compounds of formula I lower serum cholesterol, they are therapeutically useful in the treatment of hyperlipidemia.

Postopek v smislu izuma za zdravljenje hiperlipidemije obsega dajanje sesalcu, vključno človeku, ki to potrebuje, učinkovito količino spojine s formulo I.The method of the invention for treating hyperlipidemia comprises administering to the mammal, including a human in need thereof, an effective amount of a compound of formula I.

Učinkovita antihiperlipidemična količina spojine s formulo I ali njene farmacevtsko sprejemljive soli, hidrata ali solvata (tj. aktivne sestavine) je koristna pri zdravljenju, ki je profilaktično ali terapevtsko, kateregakoli bolezenskega stanja pri sesalcu, vključno človeku, poslabšanega ali povzročenega zaradi prekomernih lipidnih nivojev. Prednostno so bolezenska stanja hiperlipidemični sindromi, aterioskleroza in transplatna arterioskleroza. Posebno prednostno je bolezensko stanje ateroskleroze.An effective antihyperlipidemic amount of a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate (i.e. active ingredient) thereof is useful in the treatment of a prophylactic or therapeutic, any disease state in a mammal, including humans, impaired or caused by excessive lipid levels. Preferably, the disease states are hyperlipidemic syndromes, atherosclerosis and transplant arteriosclerosis. Particularly preferred is the disease state of atherosclerosis.

Predloženi izum se nanaša na postopek za zdravljenje hiperlipidemije pri sesalcu, vključno človeku, ki to potrebuje, ki obsega dajanje učinkovite količine spojine s formulo I ali njene farmacevtsko sprejemljive soli, hidrata ah solvata. Predloženi izum se nanaša tudi na spojino s formulo I ah njeno farmacevtsko sprejemljivo sol, hidrat ali solvat v običajni dozirni obliki, pripravljeni s kombiniranjem spojine s formulo I ali njene farmacevtsko sprejemljive soli, hidrata ah solvata z običajnim farmacevtskim nosilcem ali razredčilom v skladu z znanimi tehnikami, opisanimi v primerih spodaj.The present invention relates to a method for treating hyperlipidemia in a mammal, including a human in need thereof, comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof. The present invention also relates to a compound of formula I ah, a pharmaceutically acceptable salt, hydrate or solvate thereof in a conventional dosage form, prepared by combining a compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof with a conventional pharmaceutical carrier or diluent in accordance with known the techniques described in the examples below.

Predloženi izum zagotavlja tudi uporabo spojine s formulo I pri izdelavi zdravila za uporabo pri zdravljenju hiperlipidemije.The present invention also provides the use of a compound of formula I in the manufacture of a medicament for use in the treatment of hyperlipidemia.

Predloženi izum zagotavlja tudi farmacevtski sestavek za uporabo pri zdravljenju hiperlipidemije, ki obsega spojino s formulo I ali njene farmacevtsko sprejemljive soli, hidrate in solvate in farmacevtsko sprejemljiv nosilec ali razredčilo.The present invention also provides a pharmaceutical composition for use in the treatment of hyperlipidemia comprising a compound of formula I or pharmaceutically acceptable salts, hydrates and solvates thereof, and a pharmaceutically acceptable carrier or diluent.

Predloženi izum zagotavlja tudi postopek za pripravo farmacevtskega sestavka, ki vsebuje farmacevtsko sprejemljiv nosilec ali razredčilo in spojino s formulo I ali njene farmacevtsko sprejemljive soli, hidrate in solvate, ki obsega združevanje omenjene spojine s farmacevtsko sprejemljivim nosilcem ali razredčilom.The present invention also provides a method for the preparation of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of formula I or pharmaceutically acceptable salts, hydrates and solvates thereof, comprising combining said compound with a pharmaceutically acceptable carrier or diluent.

Če dajemo sestavke v smislu izuma v skladu s predloženim izumom ni pričakovati nezaželenih toksikoloških učinkov.When administering the compositions of the invention according to the present invention, no undesirable toxicological effects are expected.

Strokovnjaki morajo upoštevati, da je oblika in lastnost farmacevtsko sprejemljivega nosilca ali razredčila določena s količino aktivne sestavine s katero jo kombiniramo, načinom dajanja in drugimi dobro znanimi spremenljivkami. Spojino s formulo I ali njeno farmacevtsko sprejemljivo sol, hidrat ali solvat damo sesalcu, vključno Človeku, ki potrebuje antihiperlipidemično učinkovanje, v količini, ki zadostuje, da zniža lipidno koncentracijo na želene nivoje.It will be appreciated by those skilled in the art that the form and nature of the pharmaceutically acceptable carrier or diluent is determined by the amount of active ingredient with which it is combined, the route of administration and other well known variables. The compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof is administered to a mammal, including a Human in need of antihyperlipidemic action, in an amount sufficient to lower the lipid concentration to the desired levels.

Način za dajanje spojine s formulo I ni odločilen, vendar je navadno oralno ali parenteralno, prednostno oralno dajanje. Izraz parenteralno, kot ga uporabljamo tukaj, vključuje intravenozno, intramuskularno, subkutano, intranazalno, intrarektalno, transdermalno, intravaginalno ali intraperitonealno dajanje. Subkutana in intramuskularna oblika parenteralnega dajanja sta navadno prednostni. Dnevni parenteralni dozirni režim je prednostno od približno 0,01 mg/kg do približno 30 mg/kg celotne telesne mase, najbolj prednostno od približno 0,1 mg/kg do približno 3 mg/kg. Dnevni oralni dozirni režim je prednostno od približno 0,01 mg/kg do približno 30 mg/kg celotne telesne mase.The route of administration of the compound of Formula I is not conclusive, but is usually oral or parenteral, preferably oral administration. The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, intranasal, intrarectal, transdermal, intravaginal or intraperitoneal administration. Subcutaneous and intramuscular parenteral administration are generally preferred. The daily parenteral dosage regimen is preferably from about 0.01 mg / kg to about 30 mg / kg total body weight, most preferably from about 0.1 mg / kg to about 3 mg / kg. The daily oral dosage regimen is preferably from about 0.01 mg / kg to about 30 mg / kg total body weight.

Prednostno vsaka parenteralna dozirna enota vsebuje aktivno sestavino v količini od približno 0,1 mg do približno 200 mg. Prednostno vsaka oralna dozirna enota vsebuje aktivno sestavino v količini od približno 1 mg do približno 200 mg. Spojino s formulo I lahko formuliramo npr. kot tekočine, npr. sirupe, suspenzije ali emulzije, tablete, kapsule in pastile.Preferably, each parenteral dosage unit contains the active ingredient in an amount of from about 0.1 mg to about 200 mg. Preferably, each oral dosage unit contains the active ingredient in an amount of from about 1 mg to about 200 mg. The compound of formula I can be formulated e.g. as liquids, e.g. syrups, suspensions or emulsions, tablets, capsules and lozenges.

Tekoča formulacija je na splošno sestavljena iz suspenzije ali raztopine spojine s formulo I ali farmacevtsko sprejemljive soli v prikladnem tekočem nosilcu(ih), npr. etanolu, glicerolu, nevodnem topilu, npr. polietilenglikolu, oljih ali vodi s suspendirnim sredstvom, zaščitnim sredstvom, sredstvom za aromo ali obarvanje.The liquid formulation generally consists of a suspension or solution of a compound of formula I or a pharmaceutically acceptable salt in a suitable liquid carrier (s), e.g. ethanol, glycerol, a non-aqueous solvent, e.g. polyethylene glycol, oils or water with a suspending agent, a protective agent, a flavoring agent or a coloring agent.

Sestavek v obliki tablete lahko pripravimo z uporabo kateregakoli prikladnega nosilca(ev) na način, uporaben za pripravo trdnih formulacij. Primeri takih nosilcev vključujejo magnezijev stearat, škrob, laktozo, saharozo in celulozo.The tablet formulation can be prepared using any suitable carrier (s) in a manner useful for the preparation of solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

Sestavek v obliki kapsule lahko pripravimo z uporabo običajnih postopkov za zakapsuliranje. Npr. pelete, ki vsebujejo aktivno sestavino, lahko pripravimo z uporabo standardnih nosilcev in jih nato napolnimo v kapsule iz trde želatine; alternativno disperzijo ali suspenzijo lahko pripravimo z uporabo kateregakoli prikladnega farmacevtskega nosilca (ev), npr. vodnih gum, celuloz, silikatov ali olj, in jo nato napolnimo v kapsule iz mehke želatine.The capsule-shaped composition can be prepared using conventional encapsulation procedures. E.g. pellets containing the active ingredient can be prepared using standard carriers and then filled into hard gelatin capsules; an alternative dispersion or suspension may be prepared using any suitable pharmaceutical carrier (s), e.g. of water gums, celluloses, silicates or oils, and then filled into soft gelatin capsules.

Čeprav je možno, da dajemo aktivno sestavino samo, pa je prednostno, da je v obliki farmacevtske formulacije.Although it is possible to administer the active ingredient only, it is preferably in the form of a pharmaceutical formulation.

Strokovnjak mora upoštevati, da optimalno količino in razmike individualnih doziranj spojine s formulo I ali njene farmacevtsko sprejemljive soli, hidrata ali solvata določimo glede na naravo in obsežnost stanja, ki ga zdravimo, obliko, način in mesto dajanja in posebnosti pacienta, ki ga zdravimo, in da te optimume lahko določimo z običajnimi tehnikami. Prav tako je potrebno upoštevati, da optimalni potek zdravljenja, tj. število doziranj spojine s formulo I ali njene farmacevtsko sprejemljive soli, hidrata ali solvata na dan in trajanje terapije lahko določi strokovnjak z uporabo običajnih testov za določevanje poteka zdravljenja.It will be appreciated by one skilled in the art that the optimal amount and intervals of individual dosages of a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof are determined by the nature and extent of the condition being treated, the form, method and site of administration and the particularity of the patient being treated, and that these optimisms can be determined by conventional techniques. It should also be borne in mind that the optimal course of treatment, ie. the number of dosages of a compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof per day and the duration of therapy may be determined by one skilled in the art using conventional tests to determine the course of treatment.

V nadaljevanju so navedeni rezultati testov spojin v smislu izuma.The results of the tests of the compounds of the invention are listed below.

Tabela ITable I

Učinek 2-[2-(dimetilamino)etil]-8,8-dipropil-2-azaspiro[4.5]dekan dihidroklorida (spojina A) na znižanje nivojev serumskega holesterola v normalno holesterolemičnih psih iz eksperimenta I.Effect of 2- [2- (dimethylamino) ethyl] -8,8-dipropyl-2-azaspiro [4.5] decane dihydrochloride (Compound A) on lowering serum cholesterol levels in normally cholesterolemic dogs from Experiment I.

Tabela ITable I

št.enote N=1/enoto units of N = 1 / unit obdelovanje processing nivo holesterola (mg/dl) na identične dni obdelovanja cholesterol level (mg / dl) on identical days of treatment -21 -21 -14 -14 -7 -7 0 0 povprečje predobde- Imran ja average predobde- Imran me 7 7 14 14 21 21 28 28 enota 1 unit 1 samica 1,0 mg/kg spojine A solitary confinement 1.0 mg / kg of compound A 170 170 149 149 156 156 147 147 156 156 134 134 148 148 123 123 131 131 enota 2 unit 2 samica 1,0 mg/kg spojine A solitary confinement 1.0 mg / kg of compound A 173 173 184 184 172 172 187 187 179 179 152 152 153 153 143 143 134 134 enota 3 unit 3 samica 1,0 mg/kg spojine A solitary confinement 1.0 mg / kg of compound A 180 180 201 201 192 192 198 198 193 193 172 172 161 161 124 124 118 118 povprečje average 174 174 178 178 173 173 177 177 176 176 153 153 154 154 130 130 128 128 *SEM * SEM ±3 ± 3 ±15 ± 15 ±10 ± 10 ±15 ± 15 ±11 ± 11 ±11 ± 11 ±4 ± 4 ±7 ± 7 ±5 ± 5

*SEM: standardna napaka povprečij.* SEM: standard error of averages.

Podatki v tabeli I prikazujejo terapevtski učinek spojine A na nivoju serumskega holesterola.The data in Table I show the therapeutic effect of compound A on serum cholesterol levels.

TABELAHTABELAH

Učinek spojine A na znižanje nivojev serumskega holesterola v normalno holesterolemičnih psih iz eksperimenta II.Effect of compound A on the reduction of serum cholesterol levels in the normal cholesterolemic dogs of Experiment II.

ί, •TABELA IIί, • TABLE II

IGIG

Podatki v tabeli II prikazujejo terapevtski učinek spojine A na nivoje serumskega holesterola.The data in Table II show the therapeutic effect of compound A on serum cholesterol levels.

Poleg tega spojino s formulo I lahko sodajemo z nadaljnjimi aktivnimi sestavinami, kot npr. z drugimi spojinami, znanimi za zdravljenje povišanih lipidnih nivojev, kot npr. acil-CoA: inhibitorji holesterol acil transferaze (ACAT), inhibitorji HMGCoA reduktaze in sekvestranti žolčne kisline.In addition, the compound of formula I can be co-administered with further active ingredients such as e.g. with other compounds known to treat elevated lipid levels, such as e.g. acyl-CoA: cholesterol acyl transferase (ACAT) inhibitors, HMGCoA reductase inhibitors and bile acid sequestrants.

Brez nadaljnje izpopolnitve smatramo, da lahko strokovnjak na osnovi predhodnega opisa uporabi predloženi izum v njegovem popolnem obsegu. Naslednji primeri so zato izdelani le za ponazoritev in nikakor ne omejujejo obsega predloženega izuma.Without further elaboration, it is believed that a person skilled in the art will be able to use the present invention to its full extent on the basis of the foregoing description. The following examples are therefore intended to illustrate and by no means limit the scope of the present invention.

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IIII

PRIMER 1 - KAPSULNI SESTAVEKEXAMPLE 1 - Capsular composition

Oralno dozirno obliko za dajanje spojine A proizvedemo s polnjenjem standardne kapsule iz trde želatine iz dveh kosov s sestavinami v deležih, prikazanih v tabeli III spodaj.The oral dosage form for administration of Compound A is produced by filling a standard two-piece hard gelatin capsule with the ingredients in portions shown in Table III below.

TABELA IIITABLE III

Sestavine KoličineIngredients Quantities

2-[2-(dimetilamino)etil]-8,8- 25 mg dipropil-2-azaspiro[4.5]dekan dihidroklorid laktoza 55 mg smukec 16 mg magnezijev stearat 4 mg2- [2- (dimethylamino) ethyl] -8.8-25 mg dipropyl-2-azaspiro [4.5] decane dihydrochloride lactose 55 mg talc 16 mg magnesium stearate 4 mg

PRIMER 2 - INJEKCIJSKI PARENTERALNI SESTAVEKEXAMPLE 2 - INJECTION PARENTERAL COMPOSITION

Injekcijsko obliko za dajanje spojine A proizvedemo z vmešanjem 1,5 mas. % 2-[2(dimetilamino)etil]-8,8-dipropil-2-azaspiro[4.5]dekan dihidroklorida v 10 vol.% propilen glikola v vodi.The injection form for administration of compound A is produced by stirring 1.5 wt. % 2- [2 (dimethylamino) ethyl] -8,8-dipropyl-2-azaspiro [4.5] decane dihydrochloride in 10% vol. Propylene glycol in water.

PRIMER 3 -TABLETNI SESTAVEKEXAMPLE 3 - TABLE COMPOSITION

Saharozo, kalcijev sulfat dihidrat in spojino A, ki so prikazani v tabeli IV spodaj, zmešamo in granuliramo v navedenih količinah z 10 % želatinsko raztopino. Mokre granule presejemo, posušimo, zmešamo s škrobom, smukcem in stearinsko kislino, presejemo in stisnemo v tableto.Sucrose, calcium sulphate dihydrate and compound A shown in Table IV below are mixed and granulated in the amounts indicated with 10% gelatin solution. The wet granules are sieved, dried, mixed with starch, talc and stearic acid, sieved and pressed into a tablet.

TABELA IVTABLE IV

Sestavine KoličineIngredients Quantities

2-[2-(dimetilamino)etil]-8,8- 20 mg dipropil-2-azaspiro[4.5]dekan dihidroklorid kalcijev sulfat dihidrat 30 mg saharoza 4 mg škrob 2 mg smukec 1 mg stearinska kislina 0,5 mg2- [2- (dimethylamino) ethyl] -8.8-20 mg dipropyl-2-azaspiro [4.5] decane dihydrochloride calcium sulfate dihydrate 30 mg sucrose 4 mg starch 2 mg talc 1 mg stearic acid 0.5 mg

Čeprav prejšnji opisi in primeri popolnoma opisujejo predloženi izum in njegove prednostne izvedbe, je razumljivo, da predloženi izum ni omejen s posebnimi prikazanimi izvedbami, ki so v obsegu naslednjih zahtevkov.Although the foregoing descriptions and examples fully describe the present invention and its preferred embodiments, it is understood that the present invention is not limited to the particular embodiments shown, which are within the scope of the following claims.

Claims

PATENT APPLICATIONS

Use of a compound of formula I wherein n is 1 or 2;

R ¹ and R ² are the same or different and are selected from straight or branched chain hydrogen or alkyl or cyclic alkyl, provided that the total number of carbon atoms in R ¹ and R ² taken together is 0 to 10; or R ¹ and R ^{2 are} combined together to form a cyclic alkyl group of 3 to 7 carbon atoms; and R ³ and R ^{4 are the} same or different and selected from hydrogen or methyl;

or a pharmaceutically acceptable salt, hydrate or solvate thereof in the manufacture of a medicament for use in the treatment of hyperlipidemia in a mammal, including humans.

Use according to claim 1, characterized in that the compound is 2- [2- (dimethylamino) ethyl] 8,8-dipropyl-2-azaspiro [4.5] decane.

Use according to claim 1, characterized in that the mammal is a human.

Use according to claim 1, characterized in that the mammal is suffering from hyperlipidemic syndrome.

Use according to claim 1, characterized in that the mammal suffers from atherosclerosis.

Use according to claim 1, characterized in that the mammal suffers from transplant arteriosclerosis.

Use according to claim 1, characterized in that the mammal needs lower cholesterol and triglyceride levels.

Use according to claim 1, characterized in that the mammal needs lower cholesterol levels.

Use according to claim 1, characterized in that the mammal needs lower triglyceride levels.

Use according to claim 1, characterized in that the mammal needs lower levels of low density lipoprotein.

Use according to claim 1, characterized in that the compound is administered orally.

Use according to claim 11, characterized in that about 0.01 mg / kg to about 30 mg / kg of the compound is administered daily.

Use according to claim 1, characterized in that the compound is administered parenterally.

Use according to claim 13, characterized in that about 0.01 mg / kg to about 30 mg / kg of the compound is administered daily.

15. A pharmaceutical composition for use in treating hyperlipidemia in a mammal, including a human, characterized in that it contains a compound of the structure:

(I) wherein n is 1 or 2;

or a pharmaceutically acceptable salt, hydrate or solvate thereof; and a pharmaceutically acceptable carrier.

The composition of claim 15, wherein the compound is 2- [2- (dimethylamino) ethyl] 8,8-dipropyl-2-azaspiro [4.5] decane.

The composition of claim 15, wherein the mammal being treated is a human.

The composition of claim 15, wherein the mammal is suffering from hyperlipidemic syndrome.

The composition of claim 15, wherein the mammal is suffering from atherosclerosis.

The composition of claim 15, wherein the mammal is suffering from transplant arteriosclerosis.

21. The composition of claim 15, wherein the mammal needs lower cholesterol and triglyceride levels.

The composition of claim 15, wherein the mammal needs lower cholesterol levels.

A composition according to claim 15, wherein the mammal needs lower triglyceride levels.

A composition according to claim 15, wherein the mammal needs lower levels of low density lipoprotein.

The composition of claim 15, wherein the compound is administered orally.

A composition according to claim 25, characterized in that about 0.01 mg / kg to about 30 mg / kg of the compound is administered daily.

Composition according to claim 15, characterized in that the compound is administered parenterally.

A composition according to claim 27, characterized in that about 0.01 mg / kg to about 30 mg / kg of the compound is administered daily.

29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of structure.