WO1999003470A1

WO1999003470A1 - Medicinal product and method for treatment and prevention of cognitive disorders

Info

Publication number: WO1999003470A1
Application number: PCT/SE1998/001386
Authority: WO
Inventors: Ross Nicholas Waters; Clas Åke SONESSON; Nils Peter Stjernlof; Bengt Ronny Anderson; Sören Lagerkvist; Lars Olov Hansson; Per Arvid Emil Carlson; Joakim Mihkel Tedroff
Original assignee: Ross Nicholas Waters; Sonesson Clas Aake; Nils Peter Stjernlof; Bengt Ronny Anderson; Lagerkvist Soeren; Lars Olov Hansson; Per Arvid Emil Carlson; Joakim Mihkel Tedroff
Priority date: 1997-07-15
Filing date: 1998-07-15
Publication date: 1999-01-28
Also published as: SE9702716D0; JP2001510156A; EP1003513A1; AU8369998A

Abstract

The invention relates to use of compounds according to formula (I) wherein n preferably is 2; R1 preferably is SO2CH3, R2 preferably is H, and R3 preferably is a C1-C8 alkyl, or pharmaceutically acceptable salts thereof for the production of a medicinal product for treatment and/or prevention of cognitive disorders. The invention also relates to methods for treatment and prevention of cognitive disorders, said method comprising administration of a compound according to formula (I).

Description

MEDICINAL PRODUCT AND METHOD FOR TREATMENT AND PREVENTION OF COGNITIVE DISORDERS

Field of the Invention

The present invention relates to the use of specific substituted 3-phenylpiperidines and 3-penylpyrrolidine analogs, for the production of a medicinal product for treatment and/or prevention of cognitive disorders, as well as to a method for treatment and/or prevention of cognitive disorders.

Background art Cognitive deficits are clinically manifested in a wide variety of CNS disorders. Successful treatment of impaired cognitive functions improve quality of life for patients suffering from e.g. dementia, schizophrenia, bipolar disease, attentional deficit disorders, hyperactiv- ity disorders and neurological disorders such as Parkinson's and Huntington's diseases.

The neurotransmitter dopamine plays a significant role in cognitive processes. Dopaminergic systems both in the caudate nucleus and in the cortex serve cognitive functions (see e.g. Kandel and Schwartz, 1985, Principles of Neural Science, 2nd ed., Elsevier Science Publishing Co., Inc., New York). It has earlier been shown that pharmacological strengthening of dopaminergic transmission in the dopaminergic systems improve cognitive func- tions (see Psychopharmacology, 3rd Generation of Progress, 1987, Ed. H. Y. Meltzer, Raven Press, New York) and that destruction of the dopaminergic systems in the frontal cortex leads to cognitive impairment (see Brozoski, T. J. et al., 1979, Science Aug. 31; 205 (4409) : 929-32) . The present invention is based on the use of substituted 3-phenylpiperidines or 3-phenylpyrrolidine analogs. Similar compounds have been described earlier. The German patent publication No. DE 4425143 discloses 2- (piperazinoalkylthio)pyrmidines and analogs thereof as dopamine D3 receptor ligands.

The American patent No. US-A-4, 259, 337 describes new 3- (3-trifluoromethylphenyl)piperidines such as 3-(3-tri- fluoromethylphenyl) -N-n-propyl-piperidine with effects upon DA receptors.

The patent publication No. WO 92/18475 discloses various phenylazacycloalkanes . In the publication it is stated that these compounds are useful for a variety of CNS disorders but, however there is no mention of treatment or prevention of cognitive disorders. Furthermore, it is stated that the disclosed compounds affect the subclasses of dopamine (DA) receptors known as D2 and D3. In patent No. US-A-5, 545, 643 it is stated that compounds affecting the D2 receptor are suitable for elimination of cognitive deficits.

US-A-5, 633, 377 it is stated that compounds affecting the D3 and D4 receptors may be useful for treatment of memory impairment of attention deficit disorders.

Finally US-A-5, 545, 755 discloses that DA autorecep- tor antagonists can be expected to be useful in treating, among other disorders, cognitive retardation in demented and elderly patients. In addition, a number of papers describing 3- substituted 3-phenylpiperidines/pyrrolidines have been published in the literature. However, none of them discuss these compounds in association with cognitive disorders. In many cognitive disorders, such as those in patients suffering from Huntington's disease, modulation of the dopamine transmission in the frontal cortex, may have beneficial effects. The above described compounds are not fully suitable for such treatment. It has earlier been described (see e.g. Arnsten et al., 1994, Psychopharmacology-Berl. Oct., 116 (2) : 143-151, and Lidow et al., 1998, TiPS 19:166-69) that the mecha- nism through which raised levels of dopamine in the cortex mediates cognitive strengthening occurs through the Dl receptor, and thus not through the D2, D3, and D4 receptors . Furthermore, it is known that the frontal cortex lacks DA autoreceptors (see e.g. Bannon et al., 1982, Nature 296:444-446), and it is thus not possible to use the DA autoreceptor antagonists described above.

Summary of the Invention

The substituted 3-phenylpiperidine and 3-phenyl- pyrrolidine analogs used according to the invention have the ability to strengthen the dopaminergic transmission in the frontal cortex through increases in extracellular dopamine levels and thus leading to indirect stimulation of dopamine receptors, particularly Dl receptors, and are thus useful in the treatment of cognitive dysfunctions in a variety of CNS disorders.

Thus, the present invention relates to use of a com- pound according to formula I

wherein n = 1-2;

Ri is S0₂R₄ , OS0₂R₄ , S0₂NR₄R₅, COR₄ , CN, CF₃, halogen, OH, or H;

R₂ in position 2 , 4 , 5 or 6 is H, F, Cl , Br , or I ;

R₃ is H, CF₃, CH₂CF₃, a Cj_.-C₈ alkyl , a C₃-C₈ cycloalkyl , a C₄-C₉ cycloalkylmethyl , a C∑-Cs alkenyl , a C₂-Ce alkynyl , 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, -(CH₂)_m-R₆ (wherein m is 1-8), or CH₂SCH₃;

R₄ and R₅, respectively, are independently H, CF₃, CH₂CF₃, a Cι-C₈ alkyl, a C₃-C₈ cycloalkyl, a C₄-C₉ cycloalkylme- thyl, a C₂-C₈ alkenyl, a C₂-C₈ alkynyl, 3, 3, 3-trifluoro- propyl, 4, 4, 4-trifluorobutyl, -(CH₂)m-R₆ (where m is 1-8), or phenyl;

R₆ is phenyl, phenyl substituted with a CN, CF₃, S0₂CH₃, halogen, CH₂CF₃, Cι-C₈ alkyl, C₃-C₈ cycloalkyl, C-C₉ cy- cloalkylmethyl, C₂-C₈ alkenyl, or C₂-C₈ alkenyl, 2-thio- phenyl, 3-thiophenyl, NR₇CONR₈R,₉, or -CONR₇R₈; R₇, R₈ and R₉, respectively, are independently H, Cι-C₈ alkyl, C₃-C₈ cycloalkyl, C4-C₉ cycloalkylmethyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or a pharmaceutically acceptable salt thereof, for the production of a medicinal product for treatment and/or prevention of cognitive disorders.

The present invention also relates to a method for treatment and/or prevention of cognitive disorders, said method comprising administration an effective amount of a compound according to formula I, or a pharmaceutically acceptable salt thereof.

Preferably, in formula I, n is 2; Ri is S0₂CH₃, R₂ is H, and R₃ is a Cι~C₈ alkyl. The compounds used according to the present invention possess pharmacological effects, direct or indirect, on dopamine receptors and are thus useful in the treatment of cognitive disorders. The compounds used according to the invention may be both racemic mixtures and the pure enantiomers. However, preferred compounds have the S absolute configuration, according to the Cahn-Ingold- Prelog priority rules. Depending on the N-substituent, some of these S-enantiomers are dextrorotatory while others are levorotatory. Detailed Description of the Invention

The term "patient" used herein refers to an individual in need of the treatment and/or prevention according to the invention. As used herein the term C_m-C_n relates to compounds consisting of m-n carbon atoms, for example a Cj.-C₈ alkyl refers to an alkyl containing 1-8 carbon atoms in any isomeric form.

The various carbon moieties are defined as follows. Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t- butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl, i-hexyl, n-heptyl, i-heptyl and n-octyl . Alkenyl refers to a radi- cal of an aliphatic unsaturated hydrocarbon having a double bond and includes both branched and unbranched forms such as ethenyl, 1-methyl-l-ethenyl, 1-propenyl, 2- propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-l- butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, l-methyl-4-pentenyl, 3-methyl-l-pentenyl, 3-methyl-2- pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 1- methyl -4-hexenyl, 3 -methyl- 1 -hexenyl, 3 -methyl- 2- hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, l-methyl-4-heptenyl, 3 -methyl-1-heptenyl, 3-methyl-2- heptenyl, 1-octenyl, 2-octenyl or 3-octenyl. Cycloalkyl refers to a radical of a saturated cyclic hydrocarbon such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

It will be apparent to persons skilled in the art that the compounds used according to the invention contain one chiral centre. The compounds according to for- ula I contain an asymmetric carbon atom in the aliphatic ring moiety (carbon 3 in the heterocyclic ring relative to phenyl ring junction) . Some of the therapeutic effects lie in the dopamine increasing properties. The scope of this invention includes both the S and the R enantiomers of the compounds according to formula I in their pure form, as well as mixtures thereof.

Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention. Illustrative acids are sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, pamoic, ethanedisulfo- nic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic, and benzoic acid. These salts are readily pre- pared by methods known in the art.

The compounds used according to the invention may e.g. be obtained by one of the methods described in the International Patent Publication WO 92/18475.

The medicinal product containing a compound accord- ing to the invention may also comprise substances used to facilitate the production of the pharmaceutical preparation or the administration of the preparations. Such substances are well known to people skilled in the art and may for example be pharmaceutically acceptable adjuvants, carriers and preservatives.

In clinical practice the compounds used according to the present invention will normally be administered orally, rectally, or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, such as the hydrochloride, lactate, acetate, sulfamate salt, in association with a pharmaceutically acceptable carrier. The use and administration to a patient to be treated in the clinic would be readily apparent to a person of ordinary skill in the art.

In therapeutical treatment an effective amount or a therapeutic amount of the compounds of the invention are from about 0.01 to about 500 mg/kg body weight daily, preferably 0.1-10 mg/kg body weight daily. The compounds may be administered in any suitable way, such as orally or parentarally. The daily dose will preferably be administered in individual dosages 1 to 4 times daily.

Preferred compounds used according to the invention are compounds wherein Ri is -H, -OH, -CN, -S0₂CH₃ or -S0₂CF₃, and R₃ is a Cι~C₈ alkyl. Those compounds have the ability to strengthen dopaminergic transmission in the frontal cortex by a mechanism including increases in extracellular dopamine levels and thus indirect stimulation of dopamine receptors, particularly Dl receptors, and will thus be useful in the treatment of cognitive dysfunctions in a variety of CNS disorders. Uses for these compounds include preventing and treating cognitive disorders. The compounds used according to the invention have high oral availability and sufficient duration of action. Both these features are beneficial for effective clinical treatment.

The utilisation of the compounds of this invention to treat cognitive disorders is shown by their ability to increase dopamine transmission in the frontal cortex and their beneficial effects on cognitive deficits e.g. in patients suffering from Huntington' s disease.

It is also possible to use the compounds according to formula I for treatment and prevention of cognitive disorders in combination with other psychological or al- ternative pharmacological treatments.

The invention is further illustrated in the example below, which in no way is intended to limit the scope of the invention.

Brief description of the drawings

In the example below reference is made to the appended drawings on which:

Fig. 1 illustrates the effect of a substance according to the invention on dopamine (DA) and 5-hydroxyindol- acetic acid (5-HIAA) brain dialysates from the frontal cortex. Fig. 2 illustrates the effect of an other substance according to the inventioh on dopamine (DA) and 5- hydroxyindolacetic acid (5-HIAA) brain dialysates from the frontal cortex. Fig. 3 illustrates the effects of a substance according to the invention on cognitive functions in patients with Huntington's disease. The effects are in this figure shown as Luria score (which is explained further below) in six patients. Fig. 4 illustrates the effects of a substance according to the invention on cognitive functions in patients with Huntington's disease. The effects are in this figure shown as the results of the verbal fluency test in seven patients. The test is fur- ther described below.

Fig. 5 illustrates the effects of a substance according to the invention on cognitive functions in patients with Huntington's disease. The effects are in this figure shown as the results of the symbol digit modalities test in six patients. The test is further described below.

Example

This example describe how to prepare the various compounds and/or perform the various processes of the invention. Those skilled in the art will promptly recognise appropriate variations from the procedures both as to re- actants and as to reaction conditions and techniques.

In the example the following experimental procedures were used.

Microdialysis : Following the placement of a small burr hole in the appropriate lbcation on the cranium over the frontal cortex (A 3.2, L 0.5 and D 4.0 according to Paxinos G., Watson C, 1986, The Rat Brain in Stereotaxic Coordinates, Second Edition, Academic Press, New York), male Sprague-Dawely rats were stereotaxically implanted with a flexible plastic dialysis probe. The rats were then allowed to recover for 48 hours before the experiment started. After connection to a perfusion pump delivering a Ringers solution containing in mmol/1: NaCl 140, CaCl₂ 1.2, KC1 3.0, MgCl₂ 1.0 and ascorbic acid 0.04, the rats were placed in an open cage allowed to move freely within its domains. The dialysates content of DA and its metabolites were analysed on a.. HPLC-EC system allowing 5 min. runs for each sample using a sample splitting technique described by Waters et al., 1993 in Eur. J. Pharma- col. 242:151-163. The test substances were dissolved in physiological saline and injected subcutaneous in the flank. The effect of the substances were studied during 3 hours. After the experiment the rats were decapitated and the brains taken out and frozen on a block of dry ice. The location of the probes was controlled by means of a Leitz freezing microtome.

Animals : The animals used in the microdialysis experiments were male rats of the Sprague-Dawley strain (Beekay, Sweden) , weighing 200-300 g. The rats were kept 5 per cage with free access to water and food (except for the starved animals for the experiments with per oral administration, who were only allowed water the last 18 h before testing) , at least one week from arrival until used in the experiments. The substances to be tested were dissolved in saline immediately before use.

Two different substances according to the invention were tested: S- (-) -3- [3- (methylsulfonyl) phenyl] -1-propyl- piperidine [below called (-) -OSU6162] , and S-(-)-3- phenyl-1-propylpiperidine [below called (-)-DS75]. The compounds according to the invention were administered to the animals in an amount of 50 μmol/kg through subcutaneous injection. The effect of the compounds on dopamine (DA) and 5-hydroxyindolacetic acid (5-HIAA) brain dialysates from the frontal cortex were studied and the results are illustrated in figure 1 [ (-) -OSU6162] and figure 2 [(-)-DS75]. The compounds were administered at time 0 and effects are studied_* during 180 min. (-)-OSU6162 were then administered intravenous in an amount of 0.5 mg/kg to study the effect on cognitive functions in six patients with Huntington's disease. The effect were estimated by use of Luria scores. The pa- tients were examined before administration (baseline) and one day following (-)-OSU6162 administration. The Luria test forms item 13 in the motor assessment in the UHDRS (Unified Huntington's Disease Rating Scale, Mov. Disord. 1996: 11; 136-142) . Luria tests the ability to perform se- quential hand movements with a scale beginning from 0 (>4 in 10 seconds, no cue) to 4 (cannot perform) . The result is illustrated in figure 3. The values are means ± S.D. The reduction in Luria score is significant at the P=0.1 level (Wilcoxon signed rank test) . The effects of the compounds according to the invention were then estimated by the Verbal Fluency test and The Symbol Digit Modalities Test (SDMT) in seven^' and six patients, respectively, with Huntington's disease.

The patients were examined before administration (at baseline) and one day following intravenous administration of 0.5 mg/kg of (-)-OSU6162.

The Verbal Fluency test used is the Controlled Oral Word Association test adopted by Benton and Hamsher (see Benton A. L., Hamsher K. deS., Multilingual aphasia ex- amination, Iowa City: University of Iowa Press, 1976) .

This test involves the production of words beginning with a particular letter in one semantic category. This test forms item 25 of the UHDRS. The result of the test is illustrated in figure 4. The values shown are means ± S.D. The increase in the Verbal Fluency test is significant at the P=0.089 level (Wilcoxon signed rank Test)

The SDMT is a version of the Digit symbol subtest adopted by Smith (see Smith A., The symbol digit modalities test: a neuropsychologic test for economic screening of learning and other cerebral disorders, Learn. Disord. 1968;3:83-89). This test forms item 26 in the UHDRS. Increased raw score indicates improvement. The result of the test is illustrated in figure 5. The values shown are means ± S.D. The increase in the SDMT is significant at the P=0.041 level (Wilcoxon signed rank test).

Claims

1. Use of a compound according to formula I

wherein n = 1-2;

Ri is S0₂R₄, OS0₂R₄, S0₂NRR₅, C0R₄, CN, CF₃, halogen, OH, or H;

R₂ in position 2, 4, 5 or 6 is H, F, Cl, Br, or I; R₃ is H, CF₃, CH₂CF₃, a C╬╣~C₈ alkyl, a C₃-C₈ cycloalkyl, a C₄-C₉ cycloalkylmethyl, a C₂-C₈ alkenyl, a C₂-C₈ alkynyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, -(CH₂)_m-R6 (wherein m is 1-8), or CH₂SCH₃;

R₄ and R₅, respectively, are independently H, CF₃, CH₂CF₃, a C╬╣-C₈ alkyl, a C₃-C₈ cycloalkyl, a C₄-C₉ cycloalkylmethyl, a C₂-C₈ alkenyl, a C₂-C₈ alkynyl, 3, 3, 3-trifluoro- propyl, 4, 4, 4-trif luorobutyl, -(CH₂)_m-R6 (where m is 1-8), or phenyl;

R₆ is phenyl, phenyl substituted with a CN, CF₃, S0₂CH₃, halogen, CH₂CF₃, C╬╣~C₈ alkyl, C₃-C₈ cycloalkyl, C₄-C₉ cycloalkylmethyl, C₂-C₈ alkenyl, or C₂-C₈ alkenyl, 2-thio- phenyl, 3-thiophenyl, NR₇CONR₈R₉, or -CONR₇R₈; R , R₈ and Rg, respectively, are independently H, C╧ç-C₈ alkyl, C₃-C₈ cycloalkyl, C₄-C9 cycloalkylmethyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or a pharmaceutically acceptable salt thereof, for the production of a medicinal product for treatment and/or prevention of cognitive disorders.

2. Use according to claim 1, wherein the compound according to formula I is a pure R enantiomer.

3. Use according to claim 1, wherein the compound according to formula I is a pure S enantiomer.

4. Use according to any one of the claims 1-3, wherein n = 2, Ri is S0₂CH₃, R₂ is H, and R₃ is a C╬╣-C₈ alkyl.

5. Use according to claim 4, wherein R₃ is n-propyl.

6. Use according to any one of the claims 1-5, wherein the medicinal product is formulated for oral administration.

7. Use according to any one of the claims 1-5, wherein the medicinal product is formulated for parental administration .

8. Use according to any one of the claims 1-7, wherein the medicinal product is intended for treatment and/or prevention of cognitive disorders caused by Huntington's disease.

9. A method for treatment and prevention of cogni- tive disorders, which comprises administration to a patient of an effective amount of a phenyl- piperidine/pyrrolidine according to formula I:

wherein n = 1-2 ;

R_x is S0₂R₄ , OS0₂R₄ , S0₂NR₄R5 , COR₄ , CN , CF₃ , halogen, OH, or H;

R₂ in position 2 , 4 , 5 or 6 is H, F, Cl , Br , or I ; R₃ is H, CF₃, CH₂CF₃, a C╬╣-C₈ alkyl, a C₃-C₈ cycloalkyl, a C₄-C₉ cycloalkylmethyl, a C₂-C₈ alkenyl, a C₂-C₈ alkynyl, 3,3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, -(CH₂)_m-R₆ (wherein m is 1-8), or CH₂SCH₃; R and R₅, respectively, are independently H, CF₃, CH₂CF₃, a Ci-Cs alkyl, a C₃-C₈ cycloalkyl, a C₄-C₉ cycloalkylmethyl, a C₂-C₈ alkenyl, a C₂-C₈ alkynyl, 3, 3, 3-trifluoro- propyl, 4, 4, 4-trifluorobutyl, -(CH₂)_m-R₆ (where m is 1-8), or phenyl; R₆ is phenyl, phenyl substituted with a CN, CF₃, S0₂CH₃, halogen, CH₂CF₃, C╬╣-C₈ alkyl, C₃-C₈ cycloalkyl, C-C₉ cycloalkylmethyl, C₂-C₈ alkenyl, or C₂-C₈ alkenyl, 2-thio- phenyl, 3-thiophenyl, NR₇CONR₈R₉, or -CONR₇R₈; R₇, R₈ and R₉, respectively, are independently H, C╬╣~C₈ al- kyl, C₃-C₈ cycloalkyl, C4-C9 cycloalkylmethyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or a pharmaceutically acceptable salt thereof.

10. A method according to* claim 9, wherein the compound according to formula I is a pure R enantiomer

11. A method according to claim 9, wherein the compound according to formula I is a pure S enantiomer.

12. A method according to any one of the claims 9- 11, wherein n = 2, Ri is S0₂CH₃, R₂ is H, and R₃ is a C╧ç-C₈ alkyl.

13. A method according to claim 12, wherein R₃ is n- propyl.

14. A method according to any one of the claim 9-13, wherein the compound according to formula I or its pharmaceutically acceptable salt is administered to a patient in a daily dose of 0.01-500 mg/kg body weight.

15. A method according to any one of the claims 9- 14, wherein the cognitive disorder to be treated or prevented is caused by Huntington's disease.