AU682707B2 - Methods of treating hyperlipidemia using azaspirane derivatives - Google Patents

Description

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AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION NAME OF APPLICANT(S): SmithKline Beecham Corporation ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

INVENTION TITLE: Methods nF trj=j.io 's a The following statement is a full description of this invention, including the best method of performing it known to me/us:- *aa.

a.

II I 1 II This invention relates to a method of treatment of hyperlipidemia in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of an azaspirane dervative.

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

Background of the Invention Badger et al., J. Med. Chem., 33., 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 the Invention This invention relates to a a method of treatment of hyperlipidemia in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a compound of the Formula

I

RI

R 3 2 N (CH,)n R 4 wherein: n is 1 or 2;

R

1 and R 2 are the same or different and are selected from hydrogen or straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained in R 1 and R 2 when taken together la- P50153-1 is 0-10; or R 1 and R 2 are joined together to from a cyclic alkyl group having 3-7 carbon atoms; and

R

3 and R 4 are the same or different and are selected from hydrogen or methyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

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

Detailed Description of the Tnvention The term "byperlipidemia" 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 S 20 treated by the presently invented methods, are; cholesterol, triglycerides and low-density lipoproteins.

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

Chem., 33, 2963-2970, (1990) and in US Patent No.

4,963,557. Pharmaceutically acceptable salts, hydrates and solvates of the compound of structure 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 2 I P50153-1

RR

(CH2)n\ R4 RitX-

N/

4

(I)

wherein: n is 1 or 2;

R

1 and R 2 are the same or different and are selected from hydrogen or straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained in R 1 and R 2 when taken together is 0-10; or R 1 and R 2 are joined together to from a cyclic alkyl group having 3-7 carbon atoms; and

R

3 and R 4 are the same or different and are selected from hydrogen or methyl; or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Preferred among the compounds of Formula I is 2-[2o(dimethylamino)ethyl]-8,8-dipropyl-2- As used herein, the term 2-[2- 20 (dimethylamino)ethyl]-8,8-diprcpyl-2-azaspiro[4.5]decane refers to a compound of the structure

H

3

H

H

3 C I

CH

3

(I)

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

3 -i P50153-1 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 of such treatment.

2-[2-(dimethylamino)ethyl]-8,8-dipropyl-2dihydrochloride (hereinafter compound A) was tested for its in viv potency in 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 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 Libitlm from an automatic watering system, and standard laboratory chow (Pruina Laboratory Cainine 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 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 in 3 groups as follows: 4 I P50153-1 Group 1 Control, dosed orally once a day with vehicle alone.

Group 2 Low dose, dosed orally once a day with 1.0 mg/kg of compound A.

Group 3 High dose, dosed orally once a day with 3.0 mg/kg of compound A.

In Experiment II dosing continued until day The cholesterol level of each dog was established on days 7, 14, 21, 28 and 35 during treatment.

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 chemistry analyzer employing Instramentation o. Laboratories commercial reagents.

The dogs treated with 2-[2-(dimethylamino)ethyl]- 8,8-dipropyl-2-azaspiro[4.5]decane dihydrochloride 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 ;levels in mammals.

Because the compounds of Formula I lower serum cholesterol they have therapeutic utility in treating .o hyperlipidemia.

The method of this invention of treating hyperlipidemia comprises administering to a mammal, including humans, in need thereof an effective amount of a compound of Formula I.

An effective antihyperlipidemic amount of a compound of Formula I or a pharmaceutically acceptable 5

I-

P50153-I salt, hydrate or solvate thereof active ingredient) is useful in treating, prophylactically or therapeutically, any disease state in a mammal, including a human, which is exacerbated or caused by excessive lipid levels. Preferably, the disease state is selected from hyperlipidemic syndromes, atherosclerosis and transplant arteriolosclerosis.

Particularly preferred is the disease state of atherosclerosis.

This invention relates to a method of treatment of hyperlipidemia in a mammal, including a human, in need thereof which comprises administering an effective amount of a compound of Formula I or a pharmaceutically 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 I 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.

The invention also 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 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.

The invention also provides for a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable carrier or diluent and a 6

I

P50153-1 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 recogrized 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 15 variables. A compound of Formula I or a e 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 20 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, transderm,,l, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. The daily parenteral dosage regimen will preferably be fiom about 0.01 mg/kg to about 30 mg/kg of total body weight, most preferably from about 0.1 mg/kg to about 3 mg/kg. The daily oral dosage regimen will preferably be from about 0.01 mg/kg to about 30 mg/kg of total body weight.

Preferably, each parenteral dosage unit will contain the active ingredient in an amount of from about 7 P50153-1 0.1 mg to about 200 mg. Preferably each oral dosage unit will contain the active ingredient in an amount of from about 1 mg to about 200 mg.

A compound of Formula I can be formulated for example as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspersion or solution of a compound of Formula I or phirmaceutically 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 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 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 Lan 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.

While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation.

8 d, P50153-1 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 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 one of skill in the art that the optimal course of treatment, 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 using conventional course of treatment determination tests.

Following ce the results of testing the compounds a• of this invention.

S Table I The effect of 2-[2-(dimethylamino)ethyl]-8,8dipropyl-2-azaspiro[4.5]decane dihydrochloride (Compound A) on lowering serum cholesterol levels in normal 25 cholesterolemic dogs from experiment I.

9 Vno" 14,vk P50153-1 Unit No.

N=l/unit Treatment Tabhle i_ Cholesterol Level -g/dl) at Identical days of Treatment -21 -14 -7 0 Pre- 7 14 21 28 treatment Smean Unit 1 Female 170 149 156 147 156 134 148 123 131 mg/kg of Compound A Unit 2 Female 173 184 172 187 179 152 153 143 134 mg/kg of Compound A Unit 3 Female 180 201 192 198 193 172 161 124 118 mg/kg of Compound A MEAN 174 178 173 177 176 153 154 130 128 SEM -3 ±15 ±10 ±15 ±11 ±11 ±4 ±7 e u The data in the above table therapeutic effect of Compound A levels.

The effect of Compound A on The effect of Compound A on demonstrates the on serum cholesterol lowering serum r rr cholesterol levels in normal cholesterolemic dogs from experiment II.

10 1 -91 ___Table II Unit No. Treatment Cholesterol level (mg/kg) at identical days of treatment N=1/unit -14 -7 0 Pre-treatment mean 7 14 21 28 Uniti1 None 153 159 156 170 160 155 153 153 155 148 Control i Unit 2 None 179 179 164 163 171 148 147 141 149 155 Female Control Unit 3 None 214 197 214 200 206 182 179 190 191 178 ______Female Control Control MEAN 182 178 178 178 179 162 160 161 165 160 Control SEM ±18 ±11 ±18 ±11 ±14 ±10 ±10 ±15 ±13 1±9 Unit 4 Female 148 164 173 216 1 75 171 169 163 150 148 Unit 5 Female 167 158 146 153 156 124 124 110 101 103 Unit 6 Female 210 251 266 270 249 226 185 190 181 179 175 191 195 213 194 174 159 154 144 143 mg/kg SEM ±18 ±30 ±36 ±34 ±28 ±29 ±18 ±23 ±23 ±22 Unit 7 Female 12 43 37 48143 112 118 106 93 86 mg/kg ofcornpound A

I__I

Unit 8 Female 11 67 63 79170 131 107 90 88 107 mg/kg of compound A Unit 9 Female 22 89 86 74278 188 160 138 139 139 mg/kg of compound A mg/kg MEAN 192_ 200_ 195_ 200 197 144 128 111 17 i11 mg/kg SEM ±361 ±45 J±4 6 ±38 1±41 ±23 ±16 ±14 1±16 1± P50153-1 The data in the above table demonstrates the therapeutic effect of Compound A on serum cholesterol levels.

In addition, the compound of Formula I can be coadministered 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 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 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.

*a 20 EXAMPLE 1 CAPSULE COMPOSITION 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.

12 LLI I I_ L J P50153-1 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 INJECTABLE 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 water.

Example 3 Tablet Composition The sucrose, calcium sulfate dihydrate and Compound 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 IY 2 Ingredients Amounts 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 13 -y I q ~_1111 P50153-1 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.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

C

o 14

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Claims (21)

1. A method of treatment of hyperlipidemia in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a compound of Formula I R 1 (CH,)n R4 (I) (I) wherein: n is 1 or 2; R 1 and R 2 are the same or different and are selected from hydrogen or straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained in R 1 and R 2 when taken together is 0-10; or R 1 and R 2 are joined together to form a cyclic alkyl group having 3-7 carbon atoms; and R 3 and R 4 are the same or different and are selected from hydrogen or methyl; or a pharmaceutically acceptable salt, hydrate or 20 solvate thereof.

2. The method of claim 1 wherein the compound is 2-[2-(dimethylamino)ethyl]-8,8-dipropyl-2- S. So *c S 5* S

3. The method of claim 1 wherein the mammal is a human.

4. The method of claim 1 wherein the mammal is afflicted with hyperlipidemic syndrome.

The method of claim 1 wherein the mammal is afflicted with atherosclerosis. 15 c~ A I_ P50153-1

6. The method of claim 1 wherein the mammal is afflicted with transplant arteriolosclerosis.

7. The method of claim 1 wherein the mammal is in need of lower cholesterol and triglyceride levels.

8. The method of claim 1 wherein the mammal is in need of lower cholesterol levels. 0

9. The method of claim 1 wherein the mammal is in need of lower triglyceride levels.

The method of claim 1 wherein the mammal is in need of lower low-density lipoprotein levels. oe oooe g 20 9

11. The method of claim 1 wherein the compound is administered orally.

12. The method of claim 11 wherein from about 0.01 to about 30 mg of compound per kg of body weight is administered per day. b e D r o

13. The method of claim 1 wherein the compound is 25 administered parenterally.

14. The method of claim 13 wherein from about 0.01 to about 30 mg of compound per kg of body weight is administered per day.

A pharmaceutical composition for use in treating hyperlipidemia in a mammal, including a human, comprising a compound of the structure: -16- I 1-4 1 I P:\OPER\I'DB\72880-94.CLM-21/7/97 -17- R /3 R N NR (CH 2 )n R 4 wherein: n is 1 or 2; R 1 and R 2 are the same or different and are selected from hydrogen or straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained in R 1 and R 2 when taken together is 0-10; or R 1 and R 2 are joined together to form a cyclic alkyl group having 3-7 carbon atoms; and R 3 and R 4 are the same or different and are selected from hydrogen or methyl; provided that the compound is not 2-[2- 15 (dimethylamino)ethyl]-8,8-dipropyl-2-azaspiro[4.5]decane, or a pharmaceutically acceptable salt, hydrate or solvate thereof; and a pharmaceutically acceptable carrier.

16. A composition according to claim 15 wherein the compound is adapted for oral administration. I

17. A composition according to claim 16 adapted for administration of about 0.01 to about 30 mg of compound per kg body weight per day.

18. A composition according to claim 15 wherein the compound is adapted for parenteral administration.

19. A composition according to claim 18 adapted for 0administration of about 0.01 to about 30 mg of compound per 19 A ^_0adiitainoabu0.1tabu30mofcmonpe P;\OPER'DB\728-.94.CLM .21/797 -18- kg of body weight per day.

A compound of the structure N N(I) S(CH z) R 4 wherein: n is 1 or 2; R 1 and R 2 are the same or different and are selected from hydrogen or straight chain, branched chain or cyclic alkyl, provided that the total number of carbon atoms contained in R and R 2 when taken together is 0-10; or R 1 and R 2 are joined together to form a cyclic alkyl group having 3-7 carbon S 15 atoms; and R 3 and R 4 are the same or different and are selected from V hydrogen or methyl; provided that the compound is not 2-[2- (dimethylamino)ethyl]-8,8-dipropyl-2-azaspiro[4.5]decane, or a pharmaceutically acceptable salt, hydrate or solvate thereof;

21. A method of claim 1, or a pharmaceutical composition of claim 15, or compound of claim substantially as hereinbefore described with reference to the Examples. DATED this TENTH day of JULY 1997 SmithKline Beecham Corporation By DAVIES COLLISON CAVE Patent Attorneys for the applicant ~IL P50153-1 ABSTRACT OF THE DISCLOSURE o e sc D r o METHODS Invented is a method of treatment of hyperlipidemia, in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of an azaspirane derivative. Also invented are pharmaceutical compositions containing an azaspirane derivative. .0e 0 0 00 -11-41