JPH07500595A - Treatment method for hyperlipidemia using azaspirans - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] A method for treating hyperlipidemia using azaspirans The present invention provides a method for treating hyperlipidemia using azaspirans. Substituted azaspiran is administered to mammals (including humans) in need of treatment for hyperlipidemia. The present invention relates to a method for treating hyperlipidemia in mammals, characterized in that:

Background of the invention Badger et al., June 7, 1991, U.S. Patent Application No. 07 /712.325 (Badger 1) is a formula.

[In the formula, m is 1 or 2; R1 and R2 are the same or different and hydrogen or straight selected from linear or branched alkyl (provided that R1 and R2 contain total carbon number taken together is 4 to 10), or R1 and R2 taken together to form a cyclic alkyl group containing 3 to 7 carbon atoms; A is absent or C, -C, alkyl: and R3 is heterocyclic or heterobicyclic and the heterocyclic or heterobicyclic ring thereby contains up to 10 rings. Carbon atom and formula: >NR' (wherein R4 is absent or hydrogen or 1-3 1 to 3 carbon atoms or a pharmaceutically acceptable salt, hydrate or solvate thereof; Disclose.

Badger (1) discloses the compound represented by formula (1) as an antihyperlipidemic agent or No patent claims have been filed.

Summary of the invention The present invention is based on the formula [In the formula, m is 1 or 2: R1 and R2 are the same or different, hydrogen or straight or branched alkyl; (However, the total number of carbon atoms contained in R1 and R2 together is 4. ~10), or R1 and R2 together contain 3 to 7 carbon atoms. form a cyclic alkyl group with

A is absent or present as C+C+alkyl. and R3 is heterocyclic or a heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring is 10 or less carbon atoms and the formula: >NR' (wherein R4 is absent or present as hydrogen or straight-chain alkyl containing 1 to 3 carbon atoms) containing 1 to 3 heteroatoms] or a pharmaceutically acceptable salt or hydrate thereof Or, an effective amount of the solvent phase for the treatment of hyperlipidemia should be administered to the patient in need of treatment of hyperlipidemia. characterized in that it is administered to mammals (including humans), This article relates to a method for treating lipidemia.

Detailed description of the invention As used in the specification and claims, the term "hyperlipidemia" refers to abnormally high levels of lipids in the blood. It means that quality exists.

The term "antihyperlipidemia" as used here refers to reducing excess lipid concentrations to desired levels. That! Taste.

Preferred among the elevated lipids treated by the method of the present invention are cholesterol triglycerides, and low-density lipoproteins.

Compounds represented by formula (1) and pharmaceutically acceptable salts, hydrates and solvates thereof The products and formulations are disclosed in U.S. Patent Application No. 07/712.325, dated June 7, 1991. No. 1, the entire disclosure of which is hereby incorporated by reference.

The compounds of the invention are prepared by the methods described below and illustrated in the Examples.

The reagents, protecting groups and functionality of the molecule must be consistent with the proposed chemical transformation. No. Steps during the synthesis must be compatible with functional groups and protecting groups.

Compounds of formula (T) are prepared as described in Scheme (1). Scheme ■ Medium, R1 ゜R2, R3 and A have the same meanings as in formula ①, and R3 is further defined as a protecting group, preferably a or contains a benzyl protecting group, and these protecting groups dissociate to form the same formula (1)! ! righteous It becomes a substituent of R3, or it dissociates and further reacts to form a substituent of R3 having the same meaning as formula (1). Becomes a substituent.

Scheme I (Jl) Formula ■ indicates the formation of a compound of formula (1). The starting acid anhydride compound is known It is synthesized by known methods from available precursors. According to scheme 1, acid-free A solution of the hydrate compound (a) and the substituted-treated amine compound are dissolved in a suitable organic solvent, preferably to a kiln or toluene to obtain a reaction mixture. While constantly removing water, The reaction mixture is stirred at reflux temperature and evaporated to give the compound of formula (b).

The compound of formula (C) can be dissolved in a suitable organic solvent such as tetrahydrofuran (THF). A suitable reducing agent, preferably aluminum hydride, is added to the dissolved compound of formula (b). Produced by adding thium.

Pharmaceutically acceptable salts and their preparation are well known to those skilled in the art. Expressed by formula (1) Preferred pharmaceutically acceptable salts for basic compounds include hydrochloride, citric acid salts, maleates, lactates, hydrobromides and sulfates; It is not limited to.

The compound represented by formula (1) may form a hydrate or a solvate.

the formation of hydrated species when a charged compound is lyophilized with water, or It is known to those skilled in the art that solvated species are formed when concentrated in solution with a suitable organic solvent. It is knowledge.

The compound of formula (1) used in the present invention is preferably such that R1 and R2 are propyl, m is 1, 8 is absent, and R3 is 4-piperinone, i.e. 8. 8-nobrovir-2-azaspiro[45]decane-2-(4-piperidine) Ru.

The present invention provides compounds of formula (1) and pharmaceutically acceptable salts or hydrates thereof or The solvate can be used to treat hyperlipidemia in mammals (including humans) requiring treatment for hyperlipidemia. Disclosed as being useful for the treatment of.

The method for treating hyperlipidemia of the present invention comprises administering an effective amount of the compound of formula (1) therefor. The method consists of administering the drug to mammals (including humans) in need of the same.

A compound of formula (+) or a pharmaceutically acceptable salt or hydrate or solvate thereof ( In other words, the effective amount of antihyperlipidemia (active ingredient) was exacerbated by excessive lipid levels. or preventive or Useful to treat therapeutically. These conditions include hyperlipidemia syndrome, atherosis Arteriosclerosis and transplant fibrillation Includes atherosclerosis. Particularly preferred are atherosclerotic tubes.

The present invention provides a compound represented by formula (1) or a pharmaceutically acceptable salt, hydrate or or a solvate for the treatment of hyperlipidemia in a patient in need of treatment of hyperlipidemia. A method for administering high blood pressure to mammals (including mammals). This article relates to a method for treating lipidemia. Compound represented by formula (1) or pharmaceutically acceptable thereof A salt, hydrate or solvate of the compound represented by formula (1) or its pharmaceutical Acceptable salts, hydrates or solvates can be prepared using known techniques (e.g. Badger (+), 1 No. 07/712.325, dated June 7, 991) Therefore, it can be prepared by combining with a conventional pharmaceutically acceptable carrier or diluent. It can be administered to such mammals (including humans) in the usual manner.

The form and characteristics of the pharmaceutically acceptable carrier or diluent are as follows: Those skilled in the art will recognize that this will depend on the amount, route of administration and other well known variables. Probably. Compound of formula (1) or a pharmaceutically acceptable salt, hydrate or solvate thereof The substance has a desirable lipid concentration in mammals (including humans) that require antihyperlipidemic action. Administered in an amount sufficient to reduce the level to a low level.

The route of administration of compounds of formula (1) is not critical, but usually oral or parenteral, preferably oral. Orally. The term parenteral as used herein includes intravenous, intramuscular, subcutaneous, and intranasal. , rectal, transdermal, intravaginal or intraperitoneal administration. Parenteral administration subcutaneous and intramuscular Intra-meat forms are generally preferred. - daily dosage is preferably about 0,01 mg/k g total body weight to about 10 mg/kg total body weight, most preferably about 0.1 mg/kg to about 1 g total body weight mg/kg.

- daily oral dosage is preferably about 0.01 mg/kg total body weight to about IQIIg /kg total weight.

Preferably, each parenteral dosage unit contains an amount of active ingredient from about 0.1 mg to about 100 mg. Contains. Preferably, each oral dosage unit contains an amount of about oIIIg to about 1001g. Contains active ingredients.

Compounds of formula (1) that are active when administered orally may be administered in liquid form, e.g. Formulated as tablets, suspensions or emulsions, tablets, capsules and lozenges be able to.

Liquid preparations, in contrast, include suspending agents, preservatives, flavoring or coloring agents, and a suitable liquid carrier. substances such as ethanol, glycerin, non-aqueous solvents such as polyethylene glycol a suspension or solution of the compound or a pharmaceutically acceptable salt in water, oil, or water; It becomes more.

Compositions in tablet form may be prepared using any suitable pharmaceutical carrier commonly used in the manufacture of solid dosage forms. It can be manufactured using the body. Such carriers include, for example, stearic acid. Includes magnesium, starch, lactose, white sugar and cellulose.

Compositions in the form of capsules can be manufactured by conventional carcelization methods. Ru. For example, using standard carriers, pellets containing the active ingredient are prepared and hardened. It can be filled into Seratin capsules. or any suitable pharmaceutical agent. bodies, for example dispersions or A suspension is prepared and the dispersion or suspension is then filled into soft gelatin capsules. can be done.

Although it is possible to administer the active ingredient alone, it is also possible to administer it as a pharmaceutical formulation. preferable.

A compound of formula (1) or a pharmaceutically acceptable salt or hydrate or solvate thereof The optimum amount and interval of individual doses will depend on the nature and extent of the condition being treated, the form of administration. , route and site, and the individual treating practitioner, such optimal conditions. Those skilled in the art will recognize that can be determined by conventional techniques. Also, the optimal treatment method, i.e., a compound of formula (1) or a pharmaceutically acceptable salt or hydrate thereof. The number of daily doses of solvate or solvate and the duration of treatment are determined by the usual The person skilled in the art will understand that the method can be ascertained by the person skilled in the art.

Furthermore, the compounds of the present invention may further contain active ingredients such as Anru CoA. Sterol antletransferase (ACAT) inhibitor, HMGCoA Redac such as tase inhibitors and bile acid sequestrants. It can be administered in combination with other compounds for the treatment of elevated lipid levels.

Without further elaboration, one skilled in the art can recognize and understand the invention from the foregoing to its fullest extent. It is thought that it can be used in Therefore, the following examples are merely examples. It is understood that the scope of the invention is not limited in any way. should be understood.

■7 Synthesis examples In the examples below, temperatures are expressed in degrees Celsius (°C).

4.4-dipropylcyclohexane-1-carboxy-1-acetic anhydride, 4.4 -diethylcyclohexane-1-carboxy-1-acetic anhydride, 4,4-dipro Pircyclohexane-1,1-0 acetic anhydride, and 4,4-diethyl fukuohe Xane-1,1-diacetic anhydride is described in U.S. Pat. No. 4,963.557. It was synthesized as follows. 4-amino-1-benzylpiperidine, aluminum hydride tium and trobinone from Aldrich Chemical Co., Ltd. (＾1d rich Chemical Co.) (Milwaukee, Rice Consin) Purchased from. 3R-pyrrolidine and 3S-pyrrolidine Organics (Atononta, Noyosia).

Example 1 2-[4-piperinonyl]-8,8-dipropyl-2-azaspiro[4,5]- Deccan dihydrochloride (i) 2-[4-(N-benzyl)piperidinyl]-8,8-dipropyl-2 -Azaspiro[4,5]-decane-1,3-decane 4,4-dipropylcyclohe In a solution of xane-1-carboxy-1-acetic anhydride (1 molar equivalent), 4 -Amino-1-benzylpiperidine (1 molar equivalent) was added. zone soyuter Using a trap, reflux the reaction mixture until 1 equivalent of water collects in the trap. Heated at temperature. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a white solid. Obtained. The crude imide was dissolved in excess ethyl acetate and then dissolved in saturated sodium bicarbonate. The product was washed twice with aqueous solution to remove any residual acid-amide. Applicable The organic layer was dried over sodium sulfate, filtered, and concentrated to give the desired imide as a white solid. I got it. Melting point 148-149℃: Yield 90-95%0 (ii) 2-[4-(N-bennol)piperidinyl]-8,8-dipropyl- 2-Azaspiro[45]-decane Mixture of lithium aluminum hydride (32 molar equivalents) in tetrahydrofuran 2-[4-(N-benzyl)piperidinyl]-8,8-dipropyl-2-a zaspiro[4,51-decane-1,3-dione (1 molar equivalent) in tetrahydrof The run solution was added dropwise. After the addition was complete, the reaction mixture was stirred for 2-6 hours. excessive The hydride was quenched with sodium sulfate decahydrate and the resulting mixture was filtered. The filtrate was concentrated to give the desired diamine as a viscous colorless oil. The oily substance , was used directly without further purification. Yield 90-95%.

(fti) 2 (4-piperidinyl)-8,8-dipropyl-2-azaspiro [4,5]-decane 2-[4-(N-bennol)piperidinyl]-8,8-dipropyl-2-azas Pyro[4,5]-decane (1 molar equivalent) in 7.5% formic acid (in methanol) of 10% palladium on carbon (0.1 molar equivalent). pearl hydrogenation system During the incubation period, the reaction mixture was heated to 5Qp until hydrogen uptake ceased (48-96 hours). Hydrogenation was carried out at room temperature under si hydrogen pressure. The catalyst was removed by Celite filtration, and the filtrate was mtia was removed under reduced pressure. The residue was dissolved in water and then made basic with 10% NaOH. It became. The resulting aqueous emulsion was extracted with ethyl ether. The organic layer is sulfurized. Dry over sodium chloride, filter, and concentrate to give the debenzyldiamine product as a colorless oil. I got it as a thing.

Yield 90-95%.

(iv) 2-(4-piperidinyl)-8,8-dipropyl-2-azaspiro[ 45]-decane dihydrochloride 2-(4-piperidinyl)-8,8-dipropyl-2-azaspiro[4,5-co The pucan was dissolved in a minimum amount of absolute ethanol and added to a cold ethanolic solution of hydrochloric acid.

Addition of a large volume of ether produced a white precipitate, which was isolated by filtration. Ta.

The white solid was recrystallized from ethanol or methanol. Melting point 298-300 °C, yield 85-90%.

Example 2 2-(4-(N-methyl)piperidinyl)-8,8-dipropyl-2-azas Pyro-[45]-decane dihydrochloride (i) 2-(4-(N-methyl)piperinonyl)-8,8-nobrogurolu 2 -Azaspiro[4,5]-decane 2-(4-piperidinyl)-8,8-dipropyl-2-azaspiro[4,5]- Decane (1 molar equivalent, prepared according to Example 1 (iii)) in acetonitrile solution to 37% aqueous formaldehyde (5 molar equivalents) and sodium anoborohydride. Dolido (1.6 molar equivalents) was added. The reaction mixture was stirred at room temperature overnight. 2N KOH was added and the reaction mixture was extracted twice with ethyl acetate. combined organic extraction Wash with brine, dry over sodium sulfate, filter, and concentrate to a yellow viscous oil. I got something like that. , MeOH/ethyl acetate/a ammonium hydroxide (74/24/1 ．． 5) as the eluent, purify the residue by silica gel chromatography using did. The product was isolated as a colorless oil. Yield 60%.

(ji) 2-(4N-methyl)piperinonyl-8,8-dipropyl-2-a Zaspiro[4,5]-decane dihydrochloride 2-(4-piperidinyl)-8,8-noprobyl-2-azaspiro[4,5]- 2’-(4-(N-methyl)piperidinyl-8,8-nobulogo instead of decane) Using Ru2-azaspiro[45]-decane and according to Example 1 (iv), the table The title compound was prepared. Melting point 332-334°C.

Example 3 2-(4-piperidinyl)-8,8-diethyl-2-azaspiro[4,5]-de Kanni hydrochloride 4. Instead of 4-diethylfuclohexane-1-carboquino-1-acetic anhydride 4. Using 4-nopropyl noclohexane-1-carboxy-1-acetic anhydride The title compound was prepared according to Example Hi-iv). Melting point: 331-332°C.

Example 4 2-(2-(4-imidazolyl)ethyl)-8,8-')propyl-2-a Zaspiro [4,5 codecane dihydrochloride] (i) 2-(2-(4-imidazolyl)ethyl)-8,8-dipropyl-2 - Azasubiro [4,51 decane Example 1 (using histamine instead of 4-amino-1-pene/rubiberidine) The title compound was prepared according to 1-iij).

(ii) 2-(2(4-imidazolyl)ethyl)-8,8-brobyl-2 -Azaspiro[4,5]decane dihydrochloride 2-(2-(4-imidazolyl)ethyl)-8,8-dipropyl-2-azas Dissolve pyro[45]decane in a minimum amount of ethanol and add HCI□+/EtoH solution. added. The dihydrochloride did not precipitate. The solution was condensed to dryness, and at 60615 mm. Placed in a vacuum oven overnight to obtain the desired dihydrochloride salt as a white solid. Yield 72 %, melting point 258-262°C.

Example 5 2-(3R-pyrroli/nyl)-8,8-')propyl-2-azaspiro[4, 5] Decane maleate (i) 2-(3R-pyrrolidinyl)-8,8-dipropyl-2-azaspiro[4 ゜5] Decane-1,3-dione 4.4-Dibropyrunclohexane-1-carboxy-1-acetic anhydride (1 mol 3R-aminopyrrolidine (1 molar equivalent) was added to a solution of 3R-aminopyrrolidine (1 molar equivalent).

Zone Neutak Trap allows the trap to collect water in the trap until an equal amount of The reaction mixture was heated to reflux temperature. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. It condensed to give a viscous dark brown oil. The crude product was dissolved in methanol and maleic A methanol solution containing acid (1 molar equivalent) was added. The volatiles are removed from the product. Removal from the Reato solution under reduced pressure gave a dark brown solid. The solid was dissolved in dichloromethane. Recrystallization from /ethyl acetate gave the pure PuJ salt as a white crystalline solid. the generation Dissolve the salt in a minimum amount of water, basify the resulting solution with 1M sodium hydroxide, Extracted with ethyl acetate. The ether extracts were combined and dried over sodium sulfate; Filter and concentrate to give the desired imide as a viscous oil. Yield 70-75%.

(ii) 2-(3R-pyrrolinonyl)-8,8-dipropyl-2-azaspiro[ 4゜5 codecane In a mixture of lithium aluminum hydride (3,2 molar equivalents) in ethyl ether , 2-(3R-pyrrolinonyl)-8,8-dipropyl-2-azaspiro[4, 5] A solution of decane-1,3-dione (1 molar equivalent) in ethyl ether was added dropwise.

After the addition was complete, the reaction mixture was stirred for 2-6 hours. Excess of the hydride is removed with sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. Reduction gave the diamine as a viscous colorless oil. Yield 80-85%.

(iii) 2-(3R-pyrrolidinyl)-8,8-dipropyl-2-azas Pyro [4゜5] Decane Dimaleato 2-(3R-pyrrolidinyl)-8,8-dipropyl-2-azaspiro[4,5] Dissolve decane in methanol and methanol containing maleic acid (2 molar equivalents) solution was added. Solvent volume was reduced under vacuum. 10% hexane solution in ethyl acetate Carefully add the solution to the product-methanol solution to obtain a white precipitate, which is filtered. isolated by. The white solid product did not require any further purification. melting point 168.5-170°C: Yield 70-80°C.

Example 6 2-(3S-pyrrolidinyl)-8,8-dipropyl-2-azaspiro[4,5] decanji male art By using 38-aminopyrrolidine instead of 3R-aminopyrrolidine The title compound was prepared according to Example 5(i-iii). Melting point 169.5-17 0°5℃.

Example 7 2-(3'-quinuclidinyl)-8,8-dipropyl-2-azaspiro[4, 5] Decane dihydrochloride (+)2-(3°-quinuclidinyl)-8,8-dipropyl-2-azaspiro[ 4゜5] Decane-1,3-dione 4.4-Noprobyrntalohexane-1-carboxyne-1-acetic anhydride (1 mol 3-aminoquinuclidine (1 molar equivalent) was added to a toluene solution of 3-aminoquinuclidine (1 molar equivalent).

Use a Zone Nyutak trap until the volume of water collected remains constant (approximately 5 time), the reaction mixture was heated to reflux with stirring and cooled. The toluet The solution was evaporated under reduced pressure and the residue was dissolved in ethyl acetate and IN sodium hydroxide solution. distributed between. The organic layer was separated, washed with water, dried (MgSO4) and evaporated to 2 -(3-quinuclidinyl)-8,8-dipropyl-2-azaspiro[4,5]de Can-1,3-dione (94%) was obtained as a yellow oil that solidified on standing. child This was used without further purification.

(ii) 2-(3'-quinuclidinyl)-8,8-dipropyl-2-azaspiro [4゜5] Decane Stirring lithium aluminum hydride (3,5 eq.) in THF at 0 °C under argon ( 2-(3°-quinuclidinyl)-8,8-dipropyl-2 -Azaspiro[4,5]decane-1,3-dione (1 molar equivalent) in THF solution The mixture was added dropwise over 45 minutes. The reaction mixture was warmed to room temperature and then stirred overnight.

Slowly add sodium sulfate decahydrate in portions to quench unreacted LAH. The resulting solid suspension was filtered and the filtrate was evaporated under reduced pressure to remove the remaining colorless oil. I got something like that.

(iit) 2-(3°-quinuclidinyl)-8,8-dipropyl-2-azas Pyro[4゜5codecani dihydrochloride 2-(3°-quinuclidinyl)-8,8-dipropyl-2-azaspiro[4,5 ] Dissolve decane in a small volume of ethanol and add saturated hydrogen chloride solution in ethanol. Ta.

Addition of a large volume of ether produces a white precipitate, which is filtered and dried. The title compound was obtained as a white amorphous solid (70% yield): mp 277-278°C. . Elemental analysis suggests that the title compound is isolated as a monohydrate. Ta.

Example 8 2-(3°-α-(8゛-methyl-8-azabicyclo(3,2,1)-8,8 -dipropyl-2-azaspiro[4,5]decane dihydrochloride (i) 3-α-amino -8-Methyl-8-azabicyclo(3,2,1)octane (3-a-aminotro bread) Tropinone (5,0 g) containing palladium on activated carbon (10%, 2,0 g) An ethanol solution of Hydrogenated at psi for 24 hours. The reaction mixture was filtered through Celite and evaporated under reduced pressure. I set it.

The colorless residual oil was used without further purification.

The above amine (0.5 g) in methanol (5 ml) was dissolved in 1 ml of phenylisothio Treated with cyanate. Stir for 30 minutes and triturate with ether. Afterwards a crystalline solid precipitated, which was filtered and recrystallized from ethyl acetate. The thiou Reid melted at 156-157℃ (A stall (^, 5toll) , E.Tucker and E.E.B. bnother), He1v, Chew, ^Cta38゜559 (195 5) and Niss Archer (S, Archer), T.R. Isu (T, R, Levis) and M.G. Unser (M, J, L) in5er), J, ^l.

Chew, Sac, 79. 4194 (1957) is endothioureid reported melting points of 153-154°C and 160-161°C, respectively).

(ii) 3-β-amino-8-methyl-8-azabicyclo(3,2,1)oc Tan (3β-aminotropane) Produced by reducing tropinone oxime with sodium/amyl alcohol. (See M.S. Hadley for exact instructions) and F.D. King (F, D, King), U, S, 4.273 ．． 778).

The corresponding β-aminotropanethioreide melted at 178-179°C (A R. Willstatler and D. Ra, Ber.

31.1202 (1898) and Nis Arthur (s, ^rther), T.R.Levis and M.G. -(M, J, Unser).

J, As, Chew, Soc, 79. 4194 (1957) is that (reported melting points of 171-172°C and 173-175°C, respectively).

(iii) 2-(3'-α-(8°-methyl-8°-azabicyclo(3,2 , 1) octane)-8,8-mbrobyl-2-azaspiro[4,5]decanni salt 3β-amino-8-methyl-8-azabi instead of the acid salt 3-aminoquinuclidine Using cyclo(3,2,1)octane (3β-aminotro/<n), Example 7 The title compound was prepared according to (i-1ii). Description of Example 7 (iii) and The dihydrochloride salt was similarly isolated with a yield of 60%. Yield, 6 as a white amorphous solid 0%; melting point 234-235°C. According to elemental analysis, the title compound is found as a monoclonal salt. Isolated here and force (suggested).

2- (3’β-8°-methyl-8°-azabicyclo(3,2,1)octane) -8゜8-dipropyl-2-azaspiro[4,5]decane dihydrochloride 3-α-amino Example 1 (i-iv ) The title compound was prepared according to the following procedure. The dihydrochloride salt was isolated as a white amorphous solid.

Melting point 245-247°C. According to elemental analysis, the title compound was isolated as the monohydrochloride salt. This suggests that

Example 10 2-(4-piperidinyl)-9,9-dipropyl-3-azaspiro[4,5]de Kanni hydrochloride 4. Substitute for 4-dipropylcyclohexane-1-carboxy-1-acetic anhydride by using 4,4-dipropylcyclohexane-1,1-0 acetic anhydride. The title compound is prepared according to Example 1 (i-iv).

capsule composition Two standard hard gelatin capsules are filled with acid in the proportions shown in Table 1 below. to prepare oral dosage forms for administering compounds of formula (I).

8.8-dipropyl-2-azaspiro[45]decane-2-25 mg (4-pipe lysine) dihydrochloride Lactose 55a+g Talc 165g Magnesium stearate 4mg Example 2 Injectable parenteral composition 15% by weight of 8,8-dipropylene in 10% by volume of propylene glycol (in water) Stir ru-2-azaspiro[45]decane-2-(4-piperidine) dihydrochloride. Injectable dosage forms for administering the compound of formula (1) are prepared by:

Example 3 tablet composition White sugar, calcium sulfate dihydrate and the compound of formula (1) shown in Table II below, ]0% gelatin solution in the proportions shown below and granulate. Sift the wet granules filtered, dried, mixed with the starch, talc and stearic acid, sieved, Compress into tablets.

8.8-:'propyl-2-azaspiro[4,5]decane-2-20ffig (4-piperi';7') dihydrochloride Calcium sulfate dihydrate 30mg White sugar 4mg Stearic acid 0.5 g The foregoing description and examples fully describe the invention and its preferred embodiments. However, the invention is limited to each disclosed embodiment within the scope of the following claims. It is understood that it is not done.

Continuation of front page (51) Int, C1,' Identification symbol Internal office reference number C07D 221/2 07431-4C4011042097602-4C 2117602-4C 4031062097602-4C 4511027602-4C 4531027602-4C I

Claims (1)

[Claims] 1. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, m is 1 or 2: R1 and R2 are the same or different, hydrogen or straight-chain or branched alkyl (However, the total number of carbon atoms contained in R1 and R2 together is 4. ~10); or R1 and R2 together contain 3 to 7 carbon atoms; forming a cyclic alkyl group having; A is absent or present as C1-C7 alkyl; and R3 is heterocyclic or a heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring is up to 10 carbon atoms and the formula: NR4, where R4 is absent or hydrogen or as a straight-chain alkyl containing 1 to 3 carbon atoms) containing 1 to 3 heteroatoms] or its pharmaceutically acceptable an effective amount of a salt, hydrate or solvate for the treatment of hyperlipidemia. Such a feed is characterized in that it is administered to a mammal (including humans) in need of treatment. Methods for treating hyperlipidemia in animals. 2. The compound is 8,8-dipropyl-2-azaspiro[4.5]decane-2-( 4-piperidine) or a pharmaceutically acceptable salt, hydrate or solvate thereof The treatment method according to claim 1. 3. 2. The method of treatment according to claim 1, wherein said mammal is suffering from hyperlipidemia syndrome. 4. The method of claim 1, wherein the mammal is suffering from atherosclerosis. Law. 5. 2. The mammal according to claim 1, wherein the mammal is suffering from transplant arteriolar sclerosis. Method of treatment. 6. A claim in which the mammal requires a reduction in cholesterol and triglyceride levels. The treatment method according to item 1. 7. 2. The method of claim 1, wherein the mammal is in need of lowering cholesterol levels. 8. 2. The method of claim 1, wherein the mammal is in need of a reduction in triglyceride levels. 9. 2. The method of claim 1, wherein said mammal is characterized by a reduction in low density riboprotein. . 10. 2. The method of treatment according to claim 1, wherein said compound is administered orally. 11. Administering from about 0.01 mg/kg to about 10 mg/kg of the compound per day The treatment method according to claim 10. 12. 2. The method of claim 1, wherein said compound is administered parenterally. 13. Administering from about 0.01 mg/kg to about 10 mg/kg of the compound per day The treatment method according to claim 12. 14. For the manufacture of pharmaceuticals for use in the treatment of hyperlipidemia in mammals (including humans) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, m is 1 or 2; R1 and R2 are the same or different, hydrogen or straight-chain or branched alkyl (However, the total number of carbon atoms contained in R1 and R2 together is 4. ~10); or R1 and R2 together contain 3 to 7 carbon atoms; forming a cyclic alkyl group having; A is absent or present as C1-C7 alkyl; and R3 is heterocyclic or a heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring is 10 carbon atoms or less and the formula; NR4 (wherein R4 is absent or hydrogen or as a straight-chain alkyl containing 1 to 3 carbon atoms) containing 1 to 3 heteroatoms] or its pharmaceutically acceptable Use of salts, hydrates or solvates. 15. The compound is 8,8-dipropyl-2-azasubiro[4,5]decane-2- (4-piperidine) or a pharmaceutically acceptable salt, hydrate or solvate thereof. 15. The use according to claim 14. 16. 15. The use according to claim 14, wherein said mammal is suffering from hyperlipidemic syndrome. 17. 15. The use according to claim 14, wherein the mammal is suffering from atherosclerosis. for. 18. 15. The mammal is suffering from transplant arteriolar sclerosis. Use of listed. 19. The mammal is in need of lowering cholesterol and triglyceride levels. Use as described in claim 14. 20. 15. The use according to claim 14, wherein said mammal is in need of lowering cholesterol levels. 21. The use according to claim 14, wherein said mammal is in need of a reduction in triglyceride levels. 22. 15. The use according to claim 14, wherein said mammal is in need of low density riboprotein reduction. . 23. 24. The use according to claim 23, wherein said compound is administered orally. 24. Administering from about 0.01 mg/kg to about 10 mg/kg of the compound per day Use according to claim 23. 25. 15. The use according to claim 14, wherein said compound is administered parenterally. 26. Administering from about 0.01 mg/kg to about 10 mg/kg of the compound per day Use according to claim 14. 27. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, m is 1 or 2: R1 and R2 are the same or different, hydrogen or straight-chain or branched alkyl (However, the total number of carbon atoms contained in R1 and R2 together is 4. ~10]; or R1 and R2 together contain 3 to 7 carbon atoms; forming a cyclic alkyl group having; A is absent or present as C1-C7 alkyl; and R2 is heterocyclic or a heterobicyclic ring, wherein said heterocyclic or heterobicyclic ring is up to 10 carbon atoms and the formula: NR4, where R4 is absent or hydrogen or as a straight-chain alkyl containing 1 to 3 carbon atoms) containing 1 to 3 heteroatoms] or its pharmaceutically acceptable a mammalian salt, hydrate or solvate, and a pharmaceutically acceptable carrier. A pharmaceutical composition for treating hyperlipidemia in humans (including humans). 28. The compound is 8,8-dipropyl-2-azaspiro[4,5]decane-2- (4-piperidine) or a pharmaceutically acceptable salt, hydrate or solvate thereof. 28. The composition according to claim 27. 29. The composition of claim 27, wherein said mammal is suffering from hyperlipidemia syndrome. 30. 28. The group according to claim 27, wherein said mammal is suffering from atherosclerosis. A product. 31. 28. The mammal is suffering from transplant arteriolar sclerosis. composition. 32. The mammal is in need of lowering cholesterol and triglyceride levels. 28. The composition according to claim 27. 33. 28. The composition of claim 27, wherein the mammal is in need of lowering cholesterol levels. 34. 28. The composition of claim 27, wherein the mammal is in need of a reduction in triglyceride levels. 35. 28. The composition of claim 27, wherein said composition requires reduction of said mammalian low density riboprotein. . 36. 28. The composition of claim 27, wherein said compound is administered orally. 37. Administer from about 0.01 mg/kg to about 10 mg/kg of the compound per day 37. The composition of claim 36. 38. 28. The composition of claim 27, wherein said compound is administered parenterally. 39. Administer from about 0.01 mg/kg to about 10 mg/kg of the compound per day 39. The composition of claim 38.