WO1998033500A1

WO1998033500A1 - Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for inhibiting senescence-associated motor impairment

Info

Publication number: WO1998033500A1
Application number: PCT/DK1998/000032
Authority: WO
Inventors: Erik Badrum Nielsen
Original assignee: Novo Nordisk A/S
Priority date: 1997-01-29
Filing date: 1998-01-28
Publication date: 1998-08-06
Also published as: ZA98681B; AU5550398A

Abstract

The present invention provides novel uses of compounds of general formula (I), wherein R?1, R4 and R5¿ are individually hydrogen, hydroxy, halogen, trifluoromethyl, C¿1-6? alkyl, C1-6 alkoxy or (tertiary amino) C1-6 alkoxy; and R?2 and R3¿ are individually hydrogen or C¿1-6? alkyl, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for inhibiting senescence-asociated motor impairment.

Description

Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for inhibiting senescense-associated motor impairment

FIELD OF THIS INVENTION

The present invention relates to the use of compounds of the general formula I for the prevention or treatment of motor impairment. The present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.

BACKGROUND OF THIS INVENTION

It has been described that dopamine receptors decline during senescence (Joseph el al. ( 1 989) Brain Res. 505, 1 95-202. Such a decline may compromise motor funtion and result in e.g. slow walking, lack of coordination and flexibility. Estrogen has been shown to specifically upregulate the number of dopamine receptors in the brain (Joseph el al., Brain Res. (1 989) 505, 1 95-202, Hruska and Nowak, Brain Res. ( 1 988) 442, 349-350, Hruska and Silbergeld, Science (1 980) 208, 1 466-1467 and Hruska, J. Neurochem. (1 986) 47, 1 908-1 91 5).

Until now, no treatment has been found which specifically improve senescence associated motor impairment. Thus there is a need for a compound, which can prevent or treat motor impairment.

Centchroman is a non-steroidal compound known to have antiestrogenic activity. It is in use in India as an oral contraceptive (see, for example, Salman et al., U.S. Patent Specification No. 4,447,622; Singh et al., Acta Endocrinal (Copenh) 1 26 ( 1 992), 444 - 450; Grubb, C JΠ Ωmi Obstet Gynecol 2. ( 1 991 ), 491 - 495; Sankaran et al., Contraception 9 (1 974), 279 - 289; Indian Patent Specification No. 1 291 87). Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int J Cancer 43 (1 989), 781 - 783. Recently, centchroman as a racemate has been found as a potent cholesterol lowering pharmaceutical expressed by a significant decrease of the serum concentrations (S.D. Bain et al., J Mio Bc Res fi (1 994), S 394).

U.S. patent 5,453,442 describes methods of lowering serum cholesterol and in- hibiting smoother muscle cell proliferation in humans and inhibiting uterine fibroid disease and endometriosis in women by administering compounds of formula I as shown therein. Furthermore, US patent 5,280,040 describes methods and pharmaceutical compositions for reducing bone loss using 3,4-diaryl chromans and their pharmaceutically acceptable salts. There is no disclosure in the patents of using the compounds to treat or prevent motor impairment.

One object of the present invention is to provide compounds which can effectively be used in the treatment or prophylaxis of motor impairment.

DETAILED DESCRIPTION OF THIS INVENTION

The present invention relates to the use of compounds of the general formula I

wherein R¹ , R⁴ and R⁵ are individually hydrogen, hydroxy, halogen, trifluoromethyl, C.,.₆ alkyl, C^ alkoxy or (tertiary amino)(C₁.₆ alkoxy); and R² and R³ are individually hydrogen or C.,.₆ alkyl, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for inhibiting se- nescense-associated motor impairment. Thus, the compounds can be used in therapy against any illness associated with motor debilitation and in therapy to improve motor performance. The compounds can be used to inhibit senescense-associated change in motor performance, e.g. improve one or more of the following, reaction time, motor coordination, speed of movement (for example with respect to running/walking/swimming etc.), improvement of muscle strenght and coordination accuracy, reduction of tremor, akinesia, improvement in facial expressiveness, improvement of ability to perform small-movement tasks (e.g. sewing, writing, using push-buttom equipment), improvement in the ability to perform rapid eye-tracking in situations with rapidly changing visual input (i.e. for example improvement in the ability to drive a car) .

The methods of inhibiting senescense-associated motor impairment provided by this invention are practised by administering to a human in need thereof a dose of a compound of formula I or a pharmaceutically acceptable salt thereof that is effective to inhibit motor impairment.

The term "inhibit" includes its generally accepted meaning which includes prohibiting, preventing, restraining, and slowing, stopping or reversing. As such, the present method includes both medical therapeutic and/or prophylatic administra- tion, as appropriate.

As used herein, the term "patient" includes men, women and children.

Within formula I, R , R^ and R° are individually hydrogen, hydroxy, halogen, trifluoromethyl, C,_₆ alkyl, C.,.₆ alkoxy or (tertiary amino)(C₁.₆ alkoxy); and R^ and

R^ are individually hydrogen or a C_j.₆ alkyl. As used herein, the term "C^ alkyl" includes straight and branched chain alkyl radicals containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec- amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like. The term "C^_₆ alk- oxy" includes straight and branched chain alkoxy radicals containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert- butoxy, n-amyloxy, sec-amyloxy, n-hexyloxy, 2-ethylbutoxy, 2,3-dimethylbutoxy and the like. "Halogen" includes chloro, fluoro, bromo and iodo. Herein, the term "(tertiary amino)(C₁.₆ alkoxy)" is a C^ alkoxy group which is substituted by a tertiary amino radical. The tertiary amino radical may be a N,N-dialkylamine such as a N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino and N,N- dibutylamino or a polymethyleneimine, e.g., piperidine, pyrrolidine, N- methylpiperazine or morpholine. Preferred compounds include those in which R^ is C-,.₆ alkoxy; R^ and R^ are C^₆ alkyl, especially methyl; R^ is hydrogen; and R ° is (tertiary amino)(C|.₆ alkoxy) of the polymethyleneimine type. Within particu- larly preferred embodiments, R^ is in the 7-position and is C,.₆ alkoxy, particularly methoxy; each of R^ and R^ is methyl, R^ is hydrogen, and R° is in the 4- position and is a (tertiary aminoMC^e alkoxy) radical such as 2-(pyrrolidin-1 - yl)ethoxy with formula II

To be included by this invention are all pharmaceutically acceptable salts of the mentioned compounds of formula I.

It is preferred to use the compounds of formula I in the transconfiguration. These compounds may be used as racemic mixtures, or the isolated d- or I- enantiomers may be used. The trans-l-enantiomers are more preferred. A particularly preferred compound for use within the present invention is centchroman having the formula IV

Although only one enantiomer is shown, it will be understood that the formula IV is used herein to designate the transconfiguration of the 3- and 4-phenyl groups and that both the d- and l-enantiomers, as well as the racemic mixture, are included.

3,4-diarylchromans are prepared according to known methods, such as those disclosed in U.S. Patent Specification No. 3,340,276 to Carney et al., U.S. Patent Specification No. 3,822,287 to Bolger, and Ray et al., J Med Chem 1 9 ( 1 976), 276 - 279, the contents of which are incorporated herein by reference. Conversion of the cis isomer to the trans configuration by means of an or- ganometallic base-catalyzed rearrangement is disclosed in U.S. Patent Specification No. 3,822,287. The optically active d- and l-enantiomers may be prepared as disclosed by Salman et al. in U.S. Patent Specification No. 4,447,622 (incorporated herein by reference) by forming an optically active acid salt which is subjected to alkaline hydrolysis to produce the desired enantiomer. If R² is dif- ferent from R³ and R⁴ is different from R⁵, the general formula I covers 8 optical isomers.

Within the present invention, 3,4-diarylchromans of formula I may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, in- eluding salts of organic acids and mineral acids. Examples of such salts include salts of organic acids such as formic acid, fumaric acid, maleic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like. Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sul^¬ phuric and phosphoric acids and the like. The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. A preferable salt is the hydrogen fumarate salt.

3,4-diarylchromans of formula I and their salts are useful within human and veterinary medicine, for example, in the treatment of patients suffering from motor impairment. For use within the present invention, 3,4-diarylchromans of formula I and their pharmaceutically acceptable salts are formulated with a pharmaceutically acceptable carrier to provide a medicament for parenteral, oral, nasal, rectal, subdermal or intradermal or transdermal administration according to conventional methods. Formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc. and may be provided in such forms as liquids, powders, emulsions, suppositories, liposomes, transdermal patches, controlled release, dermal implants, tablets, etc. One skilled in this art may for- mulate the compounds of formula I in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences. Gennaro, ed., Mack Publishing Co., Easton, PA, 1 990.

Oral administration is preferred. Thus, the active compound of formula I is pre- pared in a form suitable for oral administration, such as a tablet or capsule. Typically, a pharmaceutically acceptable salt of the compound of formula I is combined with a carrier and moulded into a tablet. Suitable carriers in this regard include starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate and the like. Such compositions may further include one or more auxiliary sub- stances, such as wetting agents, emulsifiers, preservatives, stabilizers, colouring additives, etc. Pharmaceutical compositions containing a compound of formula I may be administered one or more times per day or week. An effective amount of such a pharmaceutical composition is the amount that provides a clinically significant effect against motor impairment. Such amounts will depend, in part, on the particular condition to be treated, age, weight, and general health of the patient, and other factors evident to those skilled in the art. A typical daily dose will contain a non- toxic dosage range of from about 0.001 to about 75 mg/kg patient per day of a compound of the present invention.

The pharmaceutical compositions containing a compound of formula I may be administered in unit dosage form one or more times per day or week. In the alternative, they may be provided as controlled release formulations suitable for dermal implantation. Implants are formulated to provide release of active com- pound over the desired period of time, which can be up to several years. Con- trolled-release formulations are disclosed by, for example, Sanders et al., J. Pharm Sci 73 (1 964), 1 294 - 1 297, 1 984; U.S. Patent Specification No. 4,489,056; and U.S. Patent Specification No. 4,21 0,644, which are incorporated herein by reference.

Examples of preferred compounds of formula I are centchroman as a racemic mixture and as isolated l-centchroman and d-centchroman enantiomers. Furthermore, 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl-7- hydroxychroman is a preferred compound. The more preferred compound is iso- lated l-centchroman (l-3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-pyrrolidin-1 - yl)ethoxy)phenyl]-7-methoxychroman).

Examples of pharmaceutically acceptable acid addition salts are salts with non- toxic acids, either inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid, or organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid. The present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realising the invention in diverse forms thereof.

EXAMPLES

Test 1

A group of 3-20 women between the age of 60-85 are seleceted as a test group. The women exhibit at least one of the sequelae of senescence-associated motor impairment. A compound of the invention is given in the amount of 0.001 - 75 mg/kg patient per day and the sequelae are closely monitored. The dosing of the compound of the invention continues for a period of up to 3 months.

Test 2

The same procedure is used as in test 1 , except that the administration is 6 months.

Utility of the compounds of the invention is demonstrated by either total cessation of one or more sequelae of the patient or reduced severity or occurrence thereof.

Claims

1 . The use of compounds of the general formula I

wherein R¹ , R⁴ and R⁵ are individually hydrogen, hydroxy, halogen, tri- fluoromethyl, C_j.g alkyl, C_j.g alkoxy or (tertiary amino)(C.,.₆ alkoxy); and R² and R³ are individually hydrogen or C,^ alkyl, or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for inhibiting senescence-associated motor impairment.

2. The use, according to claim 1 , wherein R¹ in the compound used is C_j.g alkoxy, R² and R³ are

alkyl, R⁴ is hydrogen and R⁵ is (tertiary amino) C,.₆ alkoxy.

3. The use according to any one of claims 1 or 2 wherein R¹ is methoxy.

4. The use according to any one of claims 1 -3 wherein R² is methyl.

5. The use according to any one of claims 1 -4 wherein R³ is methyl.

6. The use according to any one of claims 1 -5 wherein R⁴ is hydrogen.

7. The use according to any one of claims 1 -6 wherein R⁵ is a group as stated in formula II below:

8. The use according to any one of claims 1 -7 wherein said compound is an isolated d- or l-enantiomer.

9. The use according to any one of the preceding claims wherein said compound has the general formula III as stated below:

wherein R , R², R³, R and R each are as defined in above claim 1 .

1 0. The use according to anyone of the preceding claims wherein said compound is 3,4-trans-2,2-dimethyl-3-phenyl-4[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl-7- hydroxychroman.

1 1 . The use according to anyone of the preceding claims wherein said compound is an isolated l-enantiomer.

1 2. The use according to claim 1 wherein said compound is centchroman 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-pyrrolidin-1 -yl)ethoxy)phenyl]-7- methoxychroman having the formula IV as stated below:

1 3. The use according to claim 1 2 wherein said compound is an isolated I- enantiomer of 3,4-tr ans-2,2-dimethyl-3-phenyl-4-[4-(2-pyrrolidin-1 - yl)ethoxy)phenyl]-7-methoxychroman.

1 4. The use according to any one of the preceding claims wherein said composition is in a form suitable for oral administration.

1 5. The use according to any one of the preceding claims wherein said compound is administered as a dose in a range from about 0,001 to 75 mg/kg pa- tient per day.

1 6. The use according to any one of the preceding claims wherein said composition is administered one or more times per day or week.

17. The use according to any one of the preceding claims wherein said composition is in the form of a dermal implant.

1 8. Method for inhibiting senescence-associated motor impairment comprising administering to a patient a clinically effective amount of a compound of above formula I stated to be used in any of the preceding use claims, or a pharmaceutically acceptable salt thereof in an amount sufficient to treat or prevent motor impairment.

1 9. A method of inhibiting senescence-associated motor impairment which method comprises administering a clinically effective amount of compounds and pharmaceutically acceptable compositions, according to previous claims to a patient in need of such a treatment.