AU2001287740A1

AU2001287740A1 - 1-amino-alkylcyclohexanes as trypanocidal agents

Info

Publication number: AU2001287740A1
Application number: AU2001287740A
Authority: AU
Inventors: Markus Gold; Aigars Jirgensons; Ivars Kalvinsh; Valerjans Kauss; John M. Kelly
Original assignee: Merz Pharma GmbH and Co KGaA
Current assignee: Merz Pharma GmbH and Co KGaA
Priority date: 2000-09-19
Filing date: 2001-09-14
Publication date: 2002-06-20
Anticipated expiration: 2021-09-14

Description

1- MINO-ALKYLCYCLOHEXANES AS TRYPANOCIDAL AGENTS Field of Invention

New use of 1-amino-alky1eyelohexanes, i.e., as anti- parasitemial, anti-trypanosomiasis, or t.rypanocidal agents . Background of the Invention

Vector control and other public health measures have a successful history of containing African trypanosomiasis. However, war, civil unrest and economic problems have resulted in a breakdown of these interventions and the estimated annual incidence is now 300,000 cases. The causative agents of human trypanosomiasis are the tsetse fly-transmitted protozoan parasites Trypanosoma brucei gambiense (western and central Africa) and Trypanosoma brucei rhodesiense (eastern and southern Africa) . In the bloodstream of infected individuals antigenic variation by the parasite prevents elimination by the immune system and the development of a vaccine is not considered feasible. The drugs used to treat trypanosomiasis are unsatisfactory. They all require hospitalization, are expensive, can fail to eradicate parasitemia and often have toxic side effects. Melarsoprol, which is used against the advanced stage of the disease that occurs once trypanosomes have invaded the central nervous system, causes 5 to 10% patient mortality due to arsenic encephalopathy. The only other drug available for clinical use against this stage of the disease, difluoromethylornithine (DFMO) , has limited efficacy against T.b. rhodesiense infections and is very expensive. In the absence of treatment, trypanosomiasis is fatal and the development of new chemotherapeutic approaches is thus a priority. Prior Art

The prior art is represented by our prior USP 6,034,134 of March 7, 2000 and our published application WO 99/01416, PCT/EP98/04026, and Parsons et al . Neuropharmacology 38., 85-108 (1999) , wherein the active compounds utilized according to the present invention are disclosed and disclosed to be NMDA receptor antagonists and anticonvulsants. We have subsequently disclosed them to be useful as 5HT-. and neuronal nicotinic receptor antagonists . The Present Invention

The present invention is directed to a new use of 1-amino-alkylcyclohexane compounds selected from the group consisting of those of the formula

wherein R* is - (CH₂)_n- (CR⁶R⁷)_π)-NR⁸R⁹ wherein n+m = 0, 1, or 2 wherein R¹ through R⁷ are independently selected from the group consisting of hydrogen and lower-alkyl (1-6C) , and wherein R⁸ and R⁹ each represent hydrogen or lower-alkyl (1-6C) or together represent lower-alkylene -(CH₂)_χ- wherein x is 2 to 5, inclusive, and enantiomers, optical isomers, hydrates, and pharmaceutically-acceptable salts thereof, as well as pharmaceutical compositions thereof, and the preparation and use of such compounds and compositions for the treatment of a living animal as antitrypanosomiasis agents and as trypanocides .

Representative of these compounds are as follows: MRZ 579: 1-Amino-1, 3 , 3 , 5 , 5-pentamethylcyclohexane, 580 : 3,3, 5, 5-Tetramethylcyclohexylmethylamine, 601 : l-Amino-l-propyl-3 ,3,5, 5-tetramethylcyclohexane, 607 : 1-Amino-1, 3,3,5 (trans) -tetramethylcyclohexane (axial amino group) ,

614: 3-Propyl-l,3 , 5, 5-tetramethylcyclohexylamine semihydrate (mixture of diastereomers ~ 1:2) 615 : 1-Amino-l, 3,5, 5-tetramethyl-3-ethylcyclohexane (mixture of diastereomers) ,

616: 1-Amino-l, 3, 5-trimethylcyclohexane (mixture of diastereomers) ,

617: 1-Amino-l, 3-dimethyl-3-propylcyclohexane (mixture of diastereomers) ,

618: l-Amino-1,3 (trans), 5 (trans) -trimethyl-3 (cis) - propylcyclohexane,

620 : 1-Amino-l, 3-dimethyl-3-ethylcyclohexane, 621 : 1-Amino-l, 3 , 3-trimethylcyclohexane, 622: cis-3-Ethyl-l, trans-3, trans-5-trimethylcyclohex- amine,

625: l-Amino-1,3 (trans) -dimethylcyclohexane, 626 : 1,3, 3-Trimethyl-5, 5-dipropylcyclohexylamine, 627: 1-Amino-l-methyl-3 (trans) propylcyclohexane,

628 : l-Methyl-3-cis-propylcyclohexylamine,

629: 1-Amino-l-methyl-3 (trans) ethylcyclohexane, 632: 1-Amino-l, 3, 3-trimethyl-5 (cis) ethylcyclohexane, 633: l-Amino-1,3, 3-trimethyl-5 (trans) ethylcyclohexane, 634 : cis-3-Propyl-l, 5 , 5-trimethylcyclohexylamine, 635: trans-3-Propyl-l, 5, 5-trimethylcyclohexylamine ,

639: N-Ethyl-1,3,3,5,5-pentamethylcyclohexylamine,

640 : N-methyl-1-Amino-l, 3 ,3,5.5-pentamethylcyclohexane, 641 : 1-Amino-l-methylcyclohexane, 642 : N,N-dimethyl-l-amino-l, 3,3,5, 5-pentamethylcyclohexane,

644: 2- (3 ,3, 5,5-Tetramethylcyclohexyl) ethylamine, 645 : 2-Methyl-l- (3,3,5, 5-tetramethylcyclohexyl) propyl-2- a ine ,

662: 2- (1,3, 3, 5, 5-Pentamethylcyclohexyl-l) ethylamine, semihydrate

705: N- (1, 3 , 3 , 5, 5-pentamethylcyclohexyl) pyrrolidine, 680: l-amino-1, (trans) , 5 (trans) -trimethylcyclohexane, 681: l-amino-1,3 (cis) ,5 (cis) -trimethylcyclohexane, .K-O,

682 : 1-amino- (1R, 5S) trans-5-ethyl-1, 3 , 3-trimethylcyclohexane,

683 : 1-amino- (IS, 5S) cis-5-ethyl-l, 3 , 3 -trimethylcyclohexane, .H₂0,

1-Amino-l, 5, 5- rimethyl-3 (cis) -isopropyl-cyclohexane , 1-Amino-l, 5, 5-trimethyl-3 (trans) -isopropyl-cyclohexane , l-Amino-l-methyl-3 (cis) -ethyl-cyclohexane , 1-Amino-l-methyl-3 (cis) -methyl-eyelohexane , l-Amino-5,5-diethyl-l,3,3-trimethyl-cyclohexane , and Also, l-amino-1,3, 3, 5 , 5-pentamethylcyclohexane, 1-amino-l, 5, 5-trimethyl-3 , 3-diethylcyclohexane, l-amino-l-ethyl-3,3,5, 5-tetramethylcyclohexane, N-ethyl-1-amino-l, 3 ,3,5, 5-pentamethylcyclohexane, N- (1, 3, 5-trimethylcyclohexyl) pyrrolidine or piperidine, N- [1 , 3 (trans) , 5 (trans) -trimethylcyclohexyl] pyrrolidine or piperidine,

N- [1 , 3 (cis) , 5 (cis) -trimethylcyclohexyl] pyrrolidine or piperidine,

N- (1, 3 , 3 , 5-tetramethylcyclohexyl) pyrrolidine or piperidine,

N- (1, 3 , 3, 5, 5-pentamethylcyclohexyl) pyrrolidine or piperidine,

N- (1, 3 ,5, 5-tetramethyl-3-ethylcyclohexyl)pyrrolidine or piperidine, N- (1, 5, 5-trimethyl-3,3-diethylcyclohexyl) pyrrolidine or piperidine,

N- (1, 3 , 3-trimethyl-cis-5-ethylcyclohexyl) pyrrolidine or piperidine,

N- [ (IS, 5S)cis-5-ethyl-l,3,3-trimethylcyclohexyl] pyrrolidine or piperidine,

N- (1, 3 , 3 -trimethyl-trans-5-ethylcyclohexyl) pyrrolidine or piperidine,

N- [ (1R, 5S) trans-5-ethyl-l, 3 , 3-trimethylcyclohexyl] pyrrolidine or piperidine,

N- (l-ethyl-3 , 3 ,'5 , 5-tetramethylcyclohexyl) pyrrolidine or piperidine, and

N- (l-propyl-3 , 3, 5, 5-tetramethylcyclohexyl) pyrrolidine or piperidine, and optical isomers, enantiomers, and the hydrochloride, hydrobromide, hydrochloride hydrate, or other pharmaceutically-acceptable salts of any of the foregoing.

Of particular interest are compounds of the foregoing formula wherein at least R¹, R⁴, and R⁵ are lower-alkyl and those compounds wherein R¹ through R⁵ are methyl, those wherein x is 4 or 5, and in particular the compound N- (1,3,3,5, 5-pentamethylcyclohexyl) pyrrolidine, and optical isomers, enantiomers, hydrates and pharmaceutically-acceptable salts thereof.

In our USP 6,034,134 of March 7, 2000, we disclosed compounds of the foregoing formula, pharmaceutical compositions thereof, and their use as MDA-receptor antagonists and anticonvulsants . It has now been found that compounds of the foregoing formula and optical isomers, enantiomers, hydrates and pharmaceutically- acceptable salts thereof, in addition to their NMDA antagonist and anticonvulsant properties, quite unpredictably possess a high degree of anti- trypanosomiasis activity, making them useful in the treatment of trypanosomiasis and as trypanocides.

SUMMARY OF THE INVENTION

What we therefore believe to be comprised by our present invention may be summarized, inter alia, in the following words:

A method-of-treating a living animal for inhibition of progression or alleviation of a condition which is alleviated by an anti-trypanosomiasis agent or trypanocide, comprising the step of administering to the said living animal an amount of a 1-aminoalkylcyclohexane compound selected from the group consisting of those of the formula

wherein R* is - (CH, i)n- (CR⁶R⁷) m-NR^aR⁹ wherein n+m = 0, 1, or 2 wherein R¹ through R⁷ are independently selected from the group consisting of hydrogen and lower-alkyl (1-6C) , wherein R⁸ and R⁹ are independently selected from the group consisting of hydrogen and lower-alkyl (1-6C) or together represent lower-alkylene -(CH₂)_χ- wherein x is 2 to 5, inclusive, and optical isomers, enantiomers, hydrates, and pharmaceutically-acceptable salts thereof, which is effective for the said purpose; such a method wherein at least R¹, R, and R⁵ are lower- alkyl ; such a method wherein R¹ through R⁵ are methyl; such a method wherein R¹ is ethyl; such a method wherein R² is ethyl; such a method wherein R³ is ethyl; such a method wherein R⁴ is ethyl; such a method wherein R⁵ is ethyl; such a method wherein R⁵ is propyl; such a method wherein R⁶ or R⁷ is methyl; such a method wherein R⁶ or R⁷ is ethyl; such a method wherein X is 4 or 5; such a method wherein the compound is selected from the group consisting of

580 : 3,3,5, 5-Tetramethylcyclohexylmethylamine, 601: 1-Amino-l-propyl-3, 3 ,5, 5-tetramethylcyclohexane, 607: l-Amino-1,3 ,3,5 (trans) -tetramethylcyclohexane (axial amino group) ,

614.- 3-Propyl-l, 3 , 5, 5-tetramethylcyclohexylamine se ihydrate (mixture of diastereomers ~ 1:2)

615 : 1-Amino-l, 3, 5, 5-tetramethyl-3-ethylcyclohexane (mixture of diastereomers) ,

617: 1-Amino-l, 3-dimethyl-3-propylcyclohexane (mixture of diastereomers) ,

618: l-Amino-1,3 (trans), 5 (trans) -trimethyl-3 (cis) - propylcyclohexane,

620: 1-Amino-1, 3-dimethyl-3-ethylcyclohexane,

621: 1-Amino-1, 3 , 3-trimethylcyclohexane,

622: cis-3-Ethyl-l, trans-3, trans-5-trimethylcyclohex- amine,

625: l-Amino-1,3 (trans) -dimethylcyclohexane,

626 : 1,3, 3-Trimethyl-5, 5-dipropylcyclohexylamine,

627: 1-Amino-l-methyl-3 (trans) propylcyclohexane,

628 : l-Methyl-3-cis-propylcyclohexylamine,

629: 1-Amino-l-methyl-3 (trans) ethylcyclohexane,

632: 1-Amino-l, 3, 3-trimethyl-5 (cis) ethylcyclohexane, 633: 1-Amino-l, 3, 3-trimethyl-5 (trans) ethylcyclohexane, 634 : cis-3-Propyl-l, 5, 5-trimethylcyclohexylamine, 635: trans-3-Propyl-l, 5, 5-trimethylcyclohexylamine , 639: N-Ethyl-1,3,3,5,5-pentamethylcyclohexylamine, 641 : 1-Amino-l-methylcyclohexane,

642: N,N-dimethyl-l-amino-l, 3,3,5, 5-pentamethylcyclohexane,

644 : 2- (3 , 3 , 5 , 5-Tetramethylcyclohexyl) ethylamine, 645: 2-Methyl-1- (3 , 3 , 5, 5-tetramethylcyclohexyl)propyl-2- amine,

662 : 2- (1, 3 , 3 , 5, 5-Pentamethylcyclohexyl-l) ethylamine, semihydrate, and optical isomers, enantiomers, hydrates and pharmaceutically-acceptable salts of any of the foregoing; and such a method wherein the compound is administered in the form of a pharmaceutical composition thereof comprising the compound in combination with one or more pharmaceutically-acceptable diluents, excipients, or carriers .

Moreover, the use of a 1-aminσalkyleyelohexane selected from the group consisting of those of the formula

wherein R* is - (CH₂) _n- (CR⁶R)_m-NR^sR⁹ wherein n+m = 0, 1, or 2 wherein R¹ through R⁷ are independently selected from the group consisting of hydrogen and lower-alkyl (1-6C) , wherein R⁸ and R⁹ are independently selected from the group consisting of hydrogen and lower-alkyl or together represent lower-alkylene -(CH₂) - wherein x is 2 to 5, inclusive, and optical isomers, enantiomers, hydrates, and pharmaceutically-acceptable salts thereof, in the manufacture of a medicament to treat a living animal for alleviation or elimination of trypanosomiasis; such a use wherein at least R, R, and R⁵ are lower-alkyl; such a use wherein R¹ through R⁵ are methyl; such a use wherein x is 4 or 5 ; such a use wherein the compound is selected from the group consisting of

580 : 3,3,5, 5-Tetramethylcyclohexylmethylamine, 601: 1-Amino-l-propyl-3, 3,5, 5-tetramethylcyclohexane, 607: 1-Amino-l, 3,3,5 (trans) -tetramethylcyclohexane (axial amino group) ,

614 : 3 -Propyl-1, 3,5, 5-tetramethylcyclohexylamine semihydrate (mixture of diastereomers ~ 1:2) 615: 1-Amino-l, 3 , 5,5-tetramethyl-3-ethylcyclohexane (mixture of diastereomers) ,

617: 1-Amino-l, 3-dimethyl-3-propylcyclohexane (mixture of diastereomers) ,

618: l-Amino-1,3 (trans), 5 (trans) -trimethyl-3 (cis) - propyleye1ohexane,

620: 1-Amino-l, 3-dimethyl-3-ethylcyclohexane, 621: 1-Amino-l, 3, 3-trimethylcyclohexane, 622: cis-3-Ethyl-l, trans-3, trans-5-trimethylcyclohex- amine,

625: l-Amino-1,3 (trans) -dimethylcyclohexane, 62 : 1,3,3 -Trimethyl-5, 5-dipropylcyclohexylamine, 627: 1-Amino-l-methyl-3 (trans) propylcyclohexane, 628 : l-Methyl-3-cis-propylcyclohexylamine, 629: 1-Amino-l-methyl-3 (trans) ethylcyclohexane, 632: 1-Amino-l, 3, 3-trimethyl-5 (cis) ethylcyclohexane, 633: 1-Amino-l, 3, 3-trimethyl-5 (trans) ethylcyclohexane, 634 : cis-3-Propyl-l, 5, 5-trimethylcyclohexylamine, 635: trans-3-Propyl-l, 5, 5-trimethylcyclohexylamine , 639 : N-Ethyl-1, 3,3,5, 5-pentamethylcyclohexylamine, 641 : 1-Amino-1-methylcyclohexane,

642 : N,N-dimethyl-1-amino-l, 3,3,5, 5-pentamethylcyclohexane, .H₂0

644: 2- (3 , 3, 5,5-Tetramethylcyclohexyl) ethylamine, 645: 2-Methyl-l- (3,3,5, 5-tetramethylcyclohexyl) propyl-2- amine,

662: 2- (1,3,3,5,5-Pentamethylcyclohexyl-l) ethylamine, semihydrate, and optical isomers, enantiomers, hydrates and pharmaceutically-acceptable salts of any of the foregoing.

THE PRESENT INVENTION IN DETAIL Background and Pharmacology

Some of us reported recently that the bloodstream form of the African trypanosome, Trypanosoma Jbrucei, is sensitive to the anti-influenza virus drug rimantadine. In this patent application, we describe the trypanocidal properties of aminoalkylcyclohexane derivatives. Six of the compounds were found to inhibit growth in vitro of bloodstream form T. brucei by greater than 90% at concentrations in the range 0.3-0.7 μg ml^"1. A correlation between structural features of the derivatives and their trypanocidal properties was observed; hydrophobic substitutions generally enhanced activity.

METHODS Synthesis

The synthesis of the novel amino-alkylcyclohexanes which are utilized according to the present invention has been described in USP 6,034,134 of March 7, 2000. Alternative Procedure

The 1-cyclic amino compounds may also be prepared by reacting the corresponding 1-free amino-alkylcyclohexane and the selected alpha, omega-dihaloalkyl compound, e.g., 1, 3-dibromopropane, 1, 4-dibromobutane, or 1,5- dibromopentane,' according to the following representative example :

N- (1,3,3,5, 5-pentamethylcvclohexyl) pyrrolidine hydrochloride

1,3,3,5, 5-pentamethylcyclohexylamine hydrochloride (12 g, 58.3 mmol), potassium carbonate (48.4 g, 350 mmol) and 1, 4-dibromobutane (7.32 ml, 61.3 mmol) were refluxed in acetonitrile (250 ml) for 60h. After cooling to r.t., the mixture was filtered and the precipitate was washed with diethyl ether (600 ml) . The filtrate was concentrated in vacuo by rotary evaporation and the residue was fractionally distilled at reduced pressure (llmm/Hg) . The fraction at 129°C was collected to obtain colorless oil (8.95 g) . This was dissolved in diethyl ether (120 ml) and 2.7 M HCl solution in diethyl ether (30 ml) was added. The resulting precipitate was filtered off, washed with diethyl ether (3*30 ml) and dried in vacuo over NaOH to give N- (1,3,3,5,5- pentamethylcyclohexyl) pyrrolidine hydrochloride hydrate (12.9 g, 68%) with m.p. 158°C. PMR spectrum: (DMSO-d6, TMS) d: 0.97 (6H, s, 3,5-CH3); 1.11 (6H,S, 3,5-CH3); 0.8 - 1.4 (2H, cyclohexane 4-CH2) 1.41 (3H, s, 1-CH3) ; 1.69 (4H, m, cyclohexane 2,6-CH2); 1.84 (4H, m, pyrrolidine 3,4-CH2); 3.20 (4H, m, pyrrolidine 2,5-CH2); 10.9 ppm (1H, br s, NH+) . Elemental analysis (C15H29n*HCl*H20) Found (%) C 65.0; H 11.7; N5.0 Calculated (%) C 64.8; H 11.6; N 5.0. Parasites and drug testing in vitro

Bloodstream form T-brucei (strain 427) were cultured in 25 cm³ flasks at 37°C in modified Iscove's medium (pH 7.4). To establish the extent of trypanocidal activity, parasites were grown for three days in the presence of test compounds (aminoalkylcyclohexane derivatives) and the concentrations which inhibited growth by 50%(IC₅₀) and 90%(IC₉₀) were determined. In these experiments, which were performed at least in triplicate, the density of untreated cultures increased from 0.25 x 10⁵ cells ml^"1 to 4 x 10⁶ cells ml^"1. After determination of cell densities at each drug concentration using a hemocytometer (Weber Scientific International Ltd) , drug sensitivity was expressed as a percentage of growth of control cells. Results

Table A shows the general structure of selected a ino-alkylcyclohexanes used in the present study.

Ta e A

Substitutions in brackets represent alternatives in racemic mixtures, e.g., CH₃(C-H₇) means CH₃ or C₃H_?. Testing in vitro

In a preliminary screen, bloodstream form T. brucei were cultured for 3 days in growth medium at pH 7.4 in the presence of aminoalkylcyclohexane derivatives at a concentration of 5 μg ml^"1. A range of activities was observed with the compounds tested. The compounds which inhibited growth by 90% or greater were then tested further to determine their IC_5Qs and IC_9Qs. Several of the compounds were found to have appreciable trypanocidal activity. In some cases, this was more than 10 times greater than had previously been observed with αi-methyl- 1-adamantane methylamine . The effects of a number of aminoalkylcyclohexane derivatives on cultured bloodstream form T.Jbrucei were investigated. The three most active of these compounds share structural similarities with each other, having aminoethyl (662 and 644 - cf . Table 1) or aminomethyl- propyl (645 - cf. Table 1) groups attached to the cyclohexane ring at position 1. They also have dimethyl substitutions at the 3 and 5 positions, a feature present in other derivatives (580, 601 and 639 - cf . Table 1) found to have an IC_go of less than 2 μg ml^"1. It can also be seen from our data that the presence of dipropyl side chains, as in compound 626 (cf. Table 1), greatly increases the trypanocidal activity. DISCUSSION

The pharmacological activity of aminoalkylcyclohexane derivatives is representatively identified in Table 1.

An essential requirement for trypanocidal activity in the alky1cyclohexane derivatives is possession of an amino group. This can be attached directly to the cyclohexane ring or be attached via a side chain at the 1 position. Compounds in which the amino group is attached only to a cyclohexane ring also exhibited considerable toxicity to trypanosomes . See Table 1.

The trypanocidal properties of aminoalkylcyclohexane compounds were enhanced by the addition of a bulky side group at position 3. A cyclohexane ring suggests that increased hydrophobicity may be an important factor in determining the activity. There was a significant correlation between hydrophobicity and trypanocidal activity with aminoalkylcyclohexanes (compare compounds 626 and 620; Table 1) . THE TABLE REPRESENTATIVE RESULTS

Table 1 Cultured bloodstream form T. brucei were incubated at 37° for 3 days in the presence of aminoalkylcyclohexane derivatives. Initially each compound was screened to determine the inhibitory effect at 5μg ml^"1 (data in brackets) . For the more active compounds, the concentrations that inhibited growth by 50% and 90% were then evaluated. Each experiment was performed in triplicate, except where indicated (++) . These data were obtained from six experiments. Values are presented as ± SD from the mean. Where stock compounds (20 mg mi^"1) were dissolved in DMSO that are indicated as (*) and (#) indicates that they were dissolved in 50:50 (v/v) EtOH:H₂0. All other compounds were dissolved in IL,0. Control cells were treated accordingly. ND stands for not done.

TABLE 1

COMPOUND ιc₉ (Inhibi ion)

( (μμαα mmll !λ i (duσ ml^" -¹) ( 5UQ ml^"1)

625 N NDD N NDD (0%)

629 N NDD N NDD (2%)

607 N NDD N NDD (17%)

627 N NDD N NDD (17%)

642 N NDD N NDD (21%)

620 N NDD N NDD (25%)

621 N NDD N NDD (40%)

622 N NDD N NDD (40%)

633 N NDD N NDD (68%)

641 N NDD N NDD (86%)

632 2 2..9922++00., . 1199 3 3..880±0. .07

635 2 2..2233++00.. . 3333 3 3..667±0. .06

618 2 2..1199++00.. . 6699 3 3..559+0. .17

617 1 1..5544++00.. . 0088 2 2..333±0. .24

628 1 1..5544++00.. . 0022 1 1..995±0. ,03

615 1 1..4455++00.. . 0077 1 1..993+0. .02

580 1 1..4444++00.. , 0099 1 1..889±0. 02

601 1 1..4433++00.. . 0088 1 1..887±0. 02

639 1 1..3377++00.. . 1199 1 1..996±0. ,03 634 0.57±0.13 0.77±0.15++

614 0.55±0.11 0.88+0.09++

*626 0.25±0.01 0.29±0.01

662 0.24±0.03 0.38+0.08++

644 0.23+0.02 0.31+0.03

*645 0.22+0.02 0.29±0.01

PHARMACEUTICAL COMPOSITIONS

The active anti-trypanosomiasis agents of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as coated or uncoated tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof -may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing twenty (20) to one hundred (100) milligrams of active ingredient or, more broadly, ten (10) to two hundred fifty (250) milligrams per tablet, are accordingly representative unit dosage forms.

METHOD OF TREATING

Due to their high degree of anti-trypanosomiasis activity and their relatively low toxicity, together presenting a favorable therapeutic index, the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, preferably concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount. Dosage ranges may be 1-1000 milligrams daily, preferably 10-500 milligrams daily, and especially 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.

EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL COMPOSITIONS With the aid of commonly used solvents, auxiliary agents and carriers, the reaction products can be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and can be therapeutically applied by the oral, rectal, parenteral, and additional routes. Representative pharmaceutical compositions follow.

(a) Tablets suitable for oral administration which contain the active ingredient may be prepared by conventional tabletting techniques.

(b) For suppositories, any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a polyethyleneglycol which is a solid at normal room temperature but which melts at or about body temperature. (c) For parental (including intravenous and subcutaneous) sterile solutions, the active ingredient together with conventional ingredients in usual amounts are employed, such as for example sodium chloride and double-distilled water q.s., according to conventional procedure, such as filtration, aseptic filling into ampoules or IV-drip bottles, and autoclaving for sterility.

Other suitable pharmaceutical compositions will be immediately apparent to one skilled in the art.

* * * * *

The following examples are given by way of illustration only and are not to be construed as limiting.

EXAMPLE 1 Tablet Formulation A suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows:

Mg .

Active Ingredient 10

Lactose 63

Microcrystalline

Cellulose 21

Talcum 4

Magnesium stearate 1

Colloidal silicon dioxide 1

EXAMPLE 2

Tablet Formulation Another suitable formulation for a tablet containing 100 mg is as follows:

Mg.

Active Ingredient 100

Potato starch 20

Polyvinylpyrrolidone 10 Film coated and colored. The film coating material consists of:

Lactose 100

Microcryst. Cellulose 80

Gelatin 10

Polyvinylpyrrolidone , crosslinked 10

Talcum 10

Magnesium stearate 2

Colloidal silicon dioxi .de 3

Color pigments 5

EXAMPLE 3

, Capsule Formulation A suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows:

Mg.

Active Ingredient 50

Corn starch 20

Dibasic calcium phosphate 50 Talcum 2

Colloidal silicon dioxide 2 filled in a gelatin capsule.

EXAMPLE 4 Solution for injection A suitable formulation for an injectable solution containing one percent of active ingredient is as follows :

Active Ingredient mg 12 Sodium chloride mg 8 Sterile water to make ml 1 EXAMPLE 5 Liquid oral formulation A suitable formulation for 1 liter of a liquid mixture containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:

G.

Active Ingredient 2

Saccharose 250

Glucose 300

Sorbitol 150

Orange flavor 10

Sunset yellow.

Purified water to make a total of 1000 ml.

EXAMPLE 6 Liquid oral formulation Another suitable formulation for 1 liter of a liquid mixture containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows:

G.

Active Ingredient 20

Tragacanth 7

Glycerol 50

Saccharose 400

Methylparaben 0.5

Propylparaben 0.05

Black currant-flavor 10

Soluble Red color 0.02 Purified water to make a total of 1000 ml.

EXAMPLE 7 Liquid oral formulation Another suitable formulation for 1 liter of a liquid mixture containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:

G.

Active Ingredient 2

Saccharose 400

Bitter orange peel tincture 20 Sweet orange peel tincture 15 Purified water to make a total of 1000 ml.

EXAMPLE 8 Aerosol formulation 180 g aerosol solution contain:

Active Ingredient 10

Oleic acid 5

Ethanol 81

Purified Water 9

Tetrafluoroethane 75

15 ml of the solution are filled into aluminum aerosol cans, capped with a dosing valve, purged with 3.0 bar.

EXAMPLE 9

TDS formulation

100 g solution contain:

_

Active Ingredient 10.0

Ethanol 57.5

Propyleneglycol 7.5

Dimethylsulfoxide 5.0

Hydroxyethylcellulose 0.4

Purified water 19.6

1.8 ml of the solution are placed on a fleece covered by an adhesive backing foil . The system is closed by a protective liner which will be removed before use. EXAMPLE 10

Nanoparticle formulation

10 g of polybutylcyanoacrylate nanoparticles contain:

__

Active Ingredient 1.0

Poloxamer 0.1

Butylcyanoacrylate 8.75

Mannitol 0.1

Sodiumchloride 0.05

Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HCl/ethanol mixture as polymerization medium. The nanoparticles in the suspension are finally lyophilized under vacuum.

The compounds of the invention thus find application in the treatment of a living animal body, especially a human, for parasitemia such as trypanosomiasis or as trypanocidal agents .

The method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated.

Use of the compounds of the present invention in the manufacture of a medicament for the treatment of a living animal for inhibition of progression or alleviation of the selected ailment or condition, particularly for parasitemia such as trypanosomiasis or as trypanocidal agents, is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament are C5 o o α. ω

H U α.

C

ra

90 - εH rd rH O o O

Claims

1. A method of treating a living animal for inhibition of progression of or for alleviation of a condition which is alleviated by an anti-trypanosomiasis agent or by a trypanocide, comprising the step of administering to the said living animal an effective amount of a 1- aminoalkylcyclohexane compound of formula

wherein:

R* is - (CH₂)_n- (CR⁶R⁷)_m-NR⁸R⁹; n+m = 0 , 1 or 2 ;

R¹ through R⁷ are independently selected from hydrogen and C_x_₆ alkyl ;

R⁸ and R⁹ are independently selected from hydrogen and C_λ_₆ alkyl or together represent a C₂-₅ alkylene group, or an optical isomer, enantiomer, hydrate, or pharmaceutically acceptable salt thereof.

2. A method of claim 1 wherein at least R¹, R⁴ and R⁵ are C^ alkyl .

3. A method of claim 2 wherein R¹ through R⁵ are methyl .

4. A method of claim 1 wherein one of R¹, R², R³, R⁴ , R⁵, R⁶ and R⁷ is ethyl.

A method of claim 1 or claim 2 wherein R⁵ is propyl

6. A method of any one of claims 1 to 3 wherein R⁶ or R⁷ is methyl.

7. A method of any one of claims 1 to 6 wherein R⁸ and R⁹ together represent a C₄ or C₅ alkylene group .

8. A method of claim 1 wherein the compound is selected from:

3,3,5, 5-tetramethylcyclohexylmethylamine, 1-amino-l-propyl-3 ,3,5, 5-tetramethylcyclohexane, 1-amino-l, 3,3,5 (trans) -tetramethylcyclohexane (axial amino group) ,

3 -propyl-1,3,5,5 -1etramethylcyclohexylamine semihydrate (mixture of the diastereomers ~ 1:2), 1-amino-l, 3,5, 5-tetramethyl-3 -ethylcyclohexane (mixture of diastereomers) ,

1-amino-l, 3 -dimethyl-3 -propylcyclohexane (mixture of diastereomers) ,

1-amino-l, 3 (trans) , 5 (trans) -trimethyl-3 (cis) - propylcyclohexane ,

1-amino-1,3-dimethyl-3 -ethylcyclohexane , 1-amino-l, 3 , 3 -trimethyl-cyclohexane, cis-3-ethyl-l, trans-3, trans-5-trimethylcyclohexylamine,

1,3, 3 -trimethyl-5 , 5-dipropylcyclohexylamine, 1-amino-l-methyl-3 (trans) propylcyclohexane, 1-methyl-3 -cis-propylcyclohexylamine, l-amino-l-methyl-3 (trans) ethylcyclohexane, 1-amino-l, 3 , 3-trimethyl-5 (cis) ethylcyclohexane, 1-amino-l, 3 , 3 -trimethyl-5 (trans) ethylcyclohexane, cis-3 -propyl-1, 5, 5-trimethylcyclohexylamine, trans-3-propyl-l, 5, 5-trimethylcyclohexylamine, N-ethyl-1, 3,3,5, 5-pentamethylcyclohexylamine, 1-amino-1-methylcyclohexane , N,N-dimethyl-1-amino-l, 3,3,5,5- pentamethylcyclohexane, 2- (3,3,5, 5-tetramethylcyclohexyl) ethylamine, 2 -methyl -1- (3,3,5, 5-tetramethylcyclohexyl) ropyl-2- amine ,

2- (1,3,3,5, 5-pentamethylcyclohexyl-l) ethylamine semihydrate, and optical isomers, enantiomers, hydrates and pharmaceutically acceptable salts of any of the foregoing.

9. A method of any one of claims 1 to 8 wherein the compound is administered in the form of a pharmaceutical composition comprising the compound in combination with one or more pharmaceutically acceptable diluents, excipients or carriers.

10. Use of a 1-aminoalkylcyclohexane as defined in any one of claims 1 to 8 , including the optical isomers, enantiomers, hydrates thereof and pharmaceutically acceptable salts, in the manufacture of a medicament for treatment of a living animal for inhibition of progression of or for alleviation of a condition which is alleviated by an anti-trypanosomiasis agent or by a trypanocide .

11. A 1-aminoalkylcyclohexane as defined in any one of claims 1 to 8 , including the optical isomers, enantiomers, hydrates thereof and pharmaceutically acceptable salts, for use in treating a condition which is alleviated by an anti-trypanosomiasis agent or by a trypanocide .