NZ264450A - Medicaments containing azaspiro [4.5] decanes for treating hyperlipidaemia - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £64450 26 4 4 5 0 Priority Date(s): Complete Specification Filed: Ciass: Q.feA. .( h-o Publication Date: 2J5 J{Jf_ jggg ' |(-v-0 jo . •%'0 N.Z. PATrivr 1 4 SEP 1994 RECEIVED NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION METHODS We, SMTTHKLINE BpECHAM CORPORATION, a corporation organized under the laws of the Commonwealth of Pennsylvania, one of the United States of America, One Franklin Plaza, Philadelphia, Pennsylvania 19103, United States of America, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- (followed by page la) 264450 METHODS This invention relates to the use of an azaspirane derivative in the manufacture of a medicament for use in the treatment of hyperlipidemia in a mammal, including a human.

This invention also relates to pharmaceutical compositions containing an azaspirane derivative.

Background of thp Invention Badger et al., J. Med. Chem.. 21, 2963-2970, (1990) describes the structure activity relationships of azaspirane derivatives in antiarthritic and suppressor cell inducing assays. The cited reference disclosed compounds found to be active and inactive in the assays utilized therein. Badger, et al. concluded that one such compound, 2-[2-(dimethylamino)ethyl]-8,8-dipropyl-2-azaspiro[4.5]decane dihydrochloride, exhibited no biologically "significant activity.

Summary of tha InventA on This invention relates to the use of a compound of the Formula I r! n \ (CH2)„ / /NV (i) wherein: n is 1 or 2; Rl and are the same or different and are selected from hydrogen and straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained in R1 and R2 when taken together - 1a - 26 4 4 5^ is 0—10/ or R-^ and are joined together to form a cyclic alkyl group having 3-7 carbon atoms; and and are the same or different and are selected from hydrogen and 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 a human.

This invention also relates to pharmacetuical compositions containing compounds of Formula I.

Detailed Description of the Invention The term "hyperlipidemia" as used in the specification and in the claims is meant the presence of an abnormally high level of lipids in the blood.

The term "antihyperlipidemic" as used herein is meant the lowering of excessive lipid concentrations to desired levels.

Preferred lipids, of which high levels thereof are treated by the presently invented methods, are; cholesterol, triglycerides and low-density lipoproteins.

Compounds of Formula (I) can be prepared by known methods such as described in Badger, et al. J. Med.

Chem.. 22., 2963-2970, (1990) and in US Patent No. 4,963,557. Pharmaceutically acceptable salts, hydrates and solvates of the compound of structure (I) are formed, when appropriate, by methods well known to those of skill in the art.

Compounds of the present invention which are useful in the treatment of hyperlipidemia and which are included in the pharmaceutical compositions of the invention are those having Formula I 26 44 wherein: n is 1 or 2; R1 and R^ are the same or different and are selected from hydrogen and straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained in r1 and R2 when taken together is 0-10; or R1 and R^ are joined together to formi a cyclic alkyl group having 3-7 carbon atoms; and 10 r3 and R^ are the same or different and are selected from hydrogen and methyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Preferred among the compounds of Formula I is 2-[2- (dimethylamino)ethyl]-8,8-dipropyl-2-azaspiro[4.5]decane. (dimethylamino)ethyl]-8,8-dipropyl-2-azaspiro[4.5]decane Preferably when the compound 2-[2-(dimethylamino)ethyl]-25 8,8-dipropyl-2-azaspiro[4.5]decane is utilized as described herein said compound will be in the form of a dihydrochloride salt.

As used herein, the term 2-[2- refers to a H3 h3 ch3 (I) P50153-1 2 6 4 4 5 It has now been discovered that compounds of Formula I and pharmaceutically acceptable salts, hydrates and solvates thereof are useful for treatment of hyperlipidemia in a mammal, including humans, in need 5 of such treatment. 2-[2-(dimethylamino)ethyl]-8,8-dipropyl-2-azaspiro[4.5]decane dihydrochloride (hereinafter compound A) was tested for its in vivo potency in 10 lowering serum cholesterol in normal cholesterolemic dogs in two experiments.

To perform experiment I a total of 3 female pure bred normal cholesterolemic beagle dogs (Marshall Animal 15 Farms, Inc., North Rose, New York) were used. The dogs weighed between 8 and 15 kilograms at the start of the study. The dogs were maintained on tap water, which was available ad libitum from an automatic watering system, and standard laboratory chow (Pruina Laboratory Cainine 20 Chow®) . The 3 dogs were set up in 3 units and dosed once a day with 1.0 mg/kg of compound A. The cholesterol level of each dog was established on days -21, -14, -7 and day 0 prior to dosing. Dosing began on day 0, after the final pretreatment cholesterol level 25 was taken, and continuted until day 28. The cholesterol levels of each dog was established on days 7, 14, 21 and 28 during treatment. The dogs were fed approximately 300 grams of the canine chow at least 1-2 hours before dosing. The dogs were fasted for approximately 21-23 30 hours prior to obtaining blood samples.

Experiment II was performed under the same procedure as experiment I. In experiment II 9 female pure bred normal cholesterolemic beagle dogs were set up 35 in 3 groups as follows: 26 * ;Group 1 ;Group 2 ;Group 3 ;Control/ dosed orally once a day with vehicle alone. ;Low dose, dosed orally once a day with 1.0 mg/kg of compound A. ;High dose, dosed orally once a day with 3.0 mg/kg of compound A. ;In Experiment II dosing continued until day 35. The cholesterol level of each dog was established on days 7, 14, 21, 28 and 35 during treatment. ;5 ;The test compound was administered in a gelatin capsule and control dogs received in an empty capsule. Serum cholesterol levels in the blood samples were determined on an Instramentation Laboratories Monarch 10 chemistry analyzer employing Instramentation Laboratories commercial reagents. ;The dogs treated with 2-[2-(dimethylamino)ethyl]-8, 8-dipropyl-2-azaspiro[4.5]decane dihydrochloride 15 realized a significant decrease in serum cholesterol levels. Thus, the administration of 2-[2-(dimethylamino)ethyl]-8,8-dipropyl-2-azaspiro[4.5]decane results in a therapeutic lowering of serum cholesterol lev-sis in mammals. ;Because the compounds of Formula I lower serum cholesterol they have therapeutic utility in treating hyperlipidemia. ;compound of Formula I or a pharmaceutically acceptable ;20 ;25 ;30 ;An effective antihyperlipidemic amount of a ;5 ;N.Z. PATENT OFFICE ;2 2 MAY 1996 ;RECEIVE© ;26 A 450 ;salt, hydrate or solvate thereof (i.e. active ingredient) is useful in treating, prophylactically or therapeutically, any disease state in a mammal, ;including a human, which is exacerbated or caused by 5 excessive lipid levels. Preferably, the disease state is selected from hyperlipidemic syndromes, atherosclerosis and transplant arteriolosclerosis. Particularly preferred is the disease state of atherosclerosis. ;10 ;The treatment of hyperlipidemia in a mammal, including a human, in need thereof comprises administering an effective amount of a compound of Formula I or a pharmaceutically 15 acceptable salt, hydrate or solvate thereof. This invention also relates to a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof in a conventional dosage form prepared by combining a compound of Formula 1 or a pharmaceutically 20 acceptable salt, hydrate or solvate thereof, with a conventional pharmaceutically acceptable carrier or diluent according to known techniques, such as described in the examples below. ;25 The invention provides for the use of a compound of the Formula I in the manufacture of a medicament for use in treating hyperlipidemia. ;The invention also provides for a pharmaceutical 30 composition for use in the treatment of hyperlipidemia which comprises a compound of Formula I or pharmaceutically acceptable salts, hydrates and solvates and a pharmaceutically acceptable carrier or diluent. ;35 The invention also provides for a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or j • ; j ' 1 I O i ' ;- 6 - < ;j 2 2 MAY 1996 ;26 4 4 ;compound of Formula I or pharmaceutically acceptable salts, hydrates and solvates thereof which comprises bringing said compound into association with the pharmaceutically acceptable carrier or diluent. ;No unacceptable toxicological effects are expected when the compositions of the invention are administered in accordance with the present invention. ;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 ingredient with which it is to be combined, ^ the route of administration and other well-known variables. A 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 activity in an amount sufficient to lower lipid concentration to desired ^ levels. ;The route of administration of a compound of Formula I is not critical but is usually oral or parenteral, preferably oral. The term parenteral as 25 used herein includes intravenous, intramuscular, ;subcutaneous, intranasal, intrarectal, transdermal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. The daily 30 parenteral dosage regimen will preferably be from 0.01 mg/kg to 30 mg/kg of total body weight, most preferably from 0.1 mg/kg to 3 mg/kg. The daily oral dosage regimen will preferably be from 0.01 mg/kg to 30 mg/kg of total body weight. ;Preferably, each parenteral dosage unit will contain the active ingredient in an amojarufe--erf'"from-r • ;10 ;35 ;7 ;26 4 4 ;0.1 mg to 200 mg. Preferably each oral dosage unit will contain the active ingredient in an amount of from 1 mg to 200 mg. ;example as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges. ;A liquid formulation will generally consist of a 10 suspension or solution of a compound of Formula I or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or 15 coloring agent. ;A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. 20 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 procedures. For 25 example, pellets 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, 30 celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. ;While it is possible for the active ingredient to be administered alone, it is preferable to present it as 35 a pharmaceutical formulation. ;5 ;A compound of Formula I can be formulated for ;8 ;P50153-1 ;2 6 4 45 0 ;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 pharmaceutically acceptable salt, hydrate or solvate thereof will be 5 determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by 10 one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof given per day and duration of therapy, can be ascertained by those skilled in the art 15 using conventional course of treatment determination tests. ;Following are the results of testing the compounds of this invention. ;20 ;Table I ;The effect of 2-[2-(dimethylamino)ethyl]-8, 8-dipropyl-2-azaspiro[4.5]decane dihydrochloride (Compound A) on lowering serum cholesterol levels in normal 25 cholesterolemic dogs from experiment I. ;- 9 - ;P50153-1 ;2 6 4 4 5 0 ;Table I ;Unit No. N=l/unit ;Treatment ;Cholesterol Level (mg/dl) at Identical days of Treatment ;-21 ;-14 ;-7 ;0 ;Pre- ;treatment mean ;7 ;14 ;21 ;28 ;Unit 1 ;Female 1.0 mg/kg of Compound A ;170 ;149 ;156 ;147 ;156 ;134 ;148 ;123 ;131 ;Unit 2 ;Female 1.0 mg/kg of Compound A ;173 ;184 ;172 ;187 ;179 ;152 ;153 ;143 ;134 ;Unit 3 ;Female 1.0 mg/kg of Compound A ;180 ;201 ;192 ;198 ;193 ;172 ;161 ;124 ;118 ;MEAN ;174 ;178 ;173 ;177 ;176 ;153 ;154 ;130 ;128 ;SEM ;±3 ;±15 ;±10 ;±15 ;±11 ;±11 ;±4 ;±7 ;±5 ;The data in the above table demonstrates the therapeutic effect of Compound A on serum cholesterol levels. ;TABLE II ;The effect of Compound A on lowering serum cholesterol levels in normal cholesterolemic dogs from experiment II. ;Table II ;Unit No. N=l/unit ;Treatment ;Cholesterol level (mg/kg) at identical days of treatment ;-21 ;-14 ;-7 ;0 ;Pre-treatment mean ;7 ;14 ;21 ;28 ;35 ;Unit 1 ;None ;Female Control ;153 ;159 ;156 ;170 ;160 ;155 ;153 ;153 ;155 ;148 ;Unit 2 ;None ;Female Control ;179 ;179 ;164 ;163 ;171 ;148 ;147 ;141 ;149 ;155 ;Unit 3 ;None ;Female Control ;214 ;197 ;214 ;200 ;206 ;182 ;179 ;190 ;191 ;178 ;Control MEAN ;182 ;178 ;178 ;178 ;179 ;162 ;160 ;161 ;165 ;160 ;Control SEM ;±18 ;±11 ;±18 ;±11 ;±14 ;±10 ;±10 ;±15 ;±13 ;±9 ;Unit 4 ;Female ;1.0 mg/kg of compound A ;148 ;164 ;173 ;216 ;175 ;171 ;169 ;163 ;150 ;148 ;Unit 5 ;Female ;1.0 mg/kg of compound A ;167 ;158 ;146 ;153 ;156 ;124 ;124 ;110 ;101 ;103 ;Unit 6 ;Female ;1.0 mg/kg of compound A ;210 ;251 ;266 ;270 ;249 ;226 ;185 ;190 ;181 ;179 ;1.0 mg/kg MEAN ;175 ;191 ;195 ;213 ;194 ;174 ;159 ;154 ;144 ;143 ;1.0 mg/kg SEM ;+18 ;+30 ;+36 ;+34 ;±28 ;±29 ;±18 ;±23 ;±23 ;±22 ;Unit 7 ;Female ;3.0 mg/kg ofcompound A ;142 ;143 ;137 ;148 ;143 ;112 ;118 ;106 ;93 ;86 ;Unit 8 ;Female ;3.0 mg/kg of compound A ;171 ;167 ;163 ;179 ;170 ;131 ;107 ;90 ;88 ;107 ;Unit 9 ;Female ;3.0 mg/kg of compound A ;262 ;289 ;286 ;274 ;278 ;188 ;160 ;138 ;139 ;139 ;3.0 mg/kg MEAN ;192 ;200 ;195 ;200 ;197 ;144 ;128 ;111 ;107 ;111 ;3.0 mg/kg SEM ;±36 ;±45 ;±46 ;±38 ;±41 ;±23 ;±16 ;±14 ;±16 ;±15 ;P50153-1 ;2 6 4 4 5 ;The data in the above table demonstrates the therapeutic effect of Compound A on serum cholesterol administered with further active ingredients/ such as other compounds known for the treatment of elevated lipid levels such as acyl-CoA: Cholesterol acyltransferase (ACAT) inhibitors, HMGCoA reductase 10 inhibitors and bile acid sequestrants. ;Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its 15 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 Compound A is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in 25 Table III, below. ;levels. ;5 ;In addition, the compound of Formula I can be co- ;20 ;EXAMPLE*. 1 ~ CAPSULF. COMPOSITION P50153-1 2 3 4 4 ; Table III INGREDIENTS AMOUNTS 2-[2-(dimethylamino)ethyl]-8,8- 25 mg dipropyl-2-azaspiro[4.5]decane dihydrochloride Lactose 55 mg Talc 16 mg Magnesium Stearate 4 mg EXAMPLE 2 - TN.TECTABLE PARENTERAL COMPOSITION An injectable form for administering Compound A is produced by stirring 1.5% by weight of 2-[2-(dimethylamino)ethyl]-8,8-dipropyl-2-azaspiro[4.5]decane dihydrochloride in 10% by volume propylene glycol in 10 water.

Example 3 - Tablet Composition The sucrose, calcium sulfate dihydrate and Compound 15 A shown in Table IV 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.

Table IV Ingredients AffiOUnt.S 2-[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

Claims (29)

P50153-1 . - 2 8 4 4 While the above descriptions and examples fully describe the invention and the preferred embodiments thereof, it is understood that the invention is not limited to the particular disclosed embodiments coming within the scope of the following claims. - 14 - what we claim is: 264450

1 . Use of a compound of Formula I: ">oq x' (CH2)/ xR4 (I) wherein: 10 n is 1 or 2; R1 and R2 are the same or different and are selected from hydrogen and straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained in r1 and R2 when taken 15 together is 0-10; or- R1 and R2 are joined together to form a cyclic alkyl group having 3-7 carbon atoms; and R3 and R4 are the same or different and are selected from hydrogen and methyl; or a pharmaceutically acceptable salt, hydrate or 20 solvate thereof; in the manufacture of a medicament for use in the treatment of hyperlipidemia in a mammal, including a human.

2. The use according to claim 1 wherein the 25 compound is 2-[2-(dimethylamino)ethyl]-8,8-dipropyl azaspiro[4.5]decane.

3. The use according to claim 1 or claim 2 wherein the mammal is a human. 30

4. The use according to claim 1 or claim 2 wherein the mammal is afflicted with hyperlipidemia syndrome. 35

5. The use according to claim 1 or claim 2 wherein the mammal is afflicted with atherosclerosis, - 15 - 264450

6. The use according to claim 1 or claim 2 wherein the mammal is afflicted with transplant arteriolosclerosis. 5

7. The use according to claim 1 or claim 2 wherein the mammal is in need of lower cholesterol and triglyceride levels.

8. The use according to claim 1 or claim 2 10 wherein the mammal is in need of lower cholesterol 3 evels.

9. The use according to claim 1 or claim 2 wherein the mammal is in need of lower triglyceride 15 levels.

10. The use according to claim 1 or claim 2 wherein the mammal is in need of lower low-density lipoprotein levels. 20

11 . The use according to any one of claims 1 to 10 wherein the medicament is administered orally.

12. The use according to claim 11 wherein from 25 0.01 mg/kg to 30 mg/kg of compound is administered per day.

13. The use according to any one of claims 1 to 10 wherein the medicament is administered parenterally. 30 35

14. The use according to claim 13 wherein from 0.01 mg/kg to 30 mg/kg of compound is administered per day. ! m z. f-wrr:;-iT office i 2 2 HAY m - 16 - ! .-.V* to 3 L

15. A pharmaceutical composition for use in treating hyperlipidemia in a mammal, including a human, comprising a compound of the structure: R\ ,XX2 V (I) wherein: 10 n is 1 or 2; R1 and R2 are the same or different and are selected from hydrogen and straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained in r1 an<j r2 when taken 15 together is 0-10; or R1 and R2 are joined together to form a cyclic alkyl group having 3-7 carbon atoms; and R3 and R4 are the same or different and are selected from hydrogen and methyl; or a pharmaceutically acceptable salt, hydrate or 20 solvate thereof; and a therapeutically acceptable carrier.

16. A composition according to claim 15 wherei the compound is 2-[2-(dimethylamino)ethyl]-8,8- 25 -dipropyl-2-azaspiro[4.5]decane.

17. A composition according to claim 15 or claim 16 wherein the mammal being treated is a human 30

18. A composition according to claim 15 or claim 16 wherein the mammal is afflicted with hyperlipidemic syndrome.

19. A composition according to claim 15 or 35 claim 16 wherein the mammal is afflicted with atherosclerosis. - 17 - 26 4 4 5

20. A composition according to claim 15 or claim 16 wherein the mammal is afflicted with transplant arteriolosclerosis. 5

21 . A composition according to claim 15 or claim 16 wherein the mammal is in need of lower cholesterol and triglyceride levels.

22. A composition according to claim 15 or 10 claim 16 wherein the mammal is in need of lower cholesterol levels.

23. A composition according to claim 15 or claim 16 wherein the mammal is in need of lower 15 triglyceride levels. 20

24. A composition according to claim 15 or claim 16 wherein the mammal is in need of lower low-density lipoprotein levels.

25. A composition according to any one of claims 15 to 24 wherein the composition is administered orally. 25

26. A composition according to claim 25 wherein the composition contains from 0.1 mg to 200 mg of compound in each dosage unit.

27. A composition according to any one of 30 claims 15 to 24 wherein the composition is administered parenterally.

28. A composition according to claim 27 wherein the composition contains from 0.1 mg to 200 mg of 35 compound in each dosage unit. N.Z. PATENT OPFSC 2 2 MAY 1996 n - 18 - RECEIVED 20 25 26 4 4 5 0

29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the structure 10 (D- 15 DATED THIS Zl DAY OF tg a. j. park & son PER AGENTS FOR THE APPLICANTS 30