WO1992006980A1

WO1992006980A1 - Compounds having n-methyltryptamine tricyclic structure for the therapy of degenerative encephalopathies

Info

Publication number: WO1992006980A1
Application number: PCT/EP1991/001949
Authority: WO
Inventors: Carlo Scolastico; Carla Procida; Camillo Maria Francesco Giulio Palazzi; Pietro Melchiorri; Silvia Scolastico
Original assignee: Depha Team S.R.L.
Priority date: 1990-10-17
Filing date: 1991-10-14
Publication date: 1992-04-30
Also published as: IT9021767A0; IT1243845B; IT9021767A1; AU8742191A

Abstract

Pseudophrynamine A and N-methyl tryptamine derivatives thereof of formula (I), the processes for the preparation thereof and pharmaceutical compositions containing them, for the treatment of pathologies of central nervous system, particularly for the treatment of cerebropathies of dysmetabolic and/or toxic origin, of cognitive disorders connected with aging, of Parkinson's and Alzheimer's diseases.

Description

COMPOUNDS HAVING N-METHYLTRYPTAMINE TRICYCLIC STRUCTURE FOR THE THERAPY OF DEGENERATIVE ENCEPHALOPATHIES

This invention refers to pseudophrynamine A as a therapeutic agent and to derivatives having N- methyltryptamine tricyclic structure, to processes for the preparation thereof and to pharmaceutical compositions containing them.

The compounds of the invention have the following general formula 1

wherein:

ishydrogen or C₁-C₄ alkyl;

R₁ is selected from:

- hydrogen;

- a COR, group wherein R₂ is a straight or branched C₁- C₇ alkyl; phenyl optionally substituted by 1-3 halogen atoms, hydroxy, methoxy, methyl, trifluoromethyl, nitro, cyano groups; benzyl or phenethyl groups wherein the phenyl portion can be substituted as reported above; - a CONHR₃ group wherein R₃ is hydrogen; straight or branched C₁ -C₇ alkyl; phenyl optionally substituted as reported above; benzyl optionally substituted at the phenyl portion as reported above;

- a CONR^aR^b group wherein R^a and R^b, which are the same or different, are straight or branched C₁-C₇ alkyl;

- a residue of formula:

wherein R is hydrogen or C₁-C₄ alkyl, with the proviso that when R₁ is said tricyclic residue, at least one of the two R groups is not hydrogen.

Compounds 1 have several asymmetric carbon atoms and therefore the invention comprises both the single enantiomers (or couples of diastereoisomers) and the racemic mixtures.

The invention also refers to the salts of compounds 1 with pharmaceutically acceptable acids, such as hydrochloric, citric, tartaric, malic acids, etc.

C₁-C₄ alkyl is preferably methyl, whereas C₁-C₇ alkyl is preferably methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl.

Phenyl groups. are preferably unsubstituted or they are substituted by halogen atoms, more preferably by one chlorine atom at the meta position.

Pseudophrynamine A and the derivatives of the invention have a high activity on the Central Nervous System, particularly against cerebropathies of dysmetabolic or toxic origin, cognitive disorders connected with aging, Parkinson's or Alzheimer's diseases.

The parent molecule of these N-methyl tryptamine derivatives is physostigmine, of formula 2,

having, inter alia, a fair inhibitory activity on acetylcholinesterase enzyme (AChE); several other physostigmine derivatives having carbamic substituents and basic residues, such as neostigmine of formula 3, are known (J. Pharmacol. Exp. Ther.; 43, 413, 1931).

Recently, a new alkaloid, named Pseudophrynamine A, of formula 4, having an N-methyl tryptamine structure and an isoprenic side-chain, has been isolated from the. skin of Australian frogs Pseudophryne coriacea (J. Org. Chem.; 53, 1222, 1988).

Now, it has been found that pseudophrynamine A and its derivatives of general formula 1 have an interesting activity on Central Nervous System, as it could be ascertained using a conventional passive avoidance test.

Male DBA/2 and C57BL/6 mice (Laboratories Charles River, Como, Italy) weighing about 25 g were used. Mice were kept in number of 8 per cage with water and food ad libitum, at constant temperature (21 Cº) with a 12:12 hour night/day cycle. Different animals were used for each test, each mouse being used only once in all of the tests.

Tests were carried out according to a standard procedure: training was carried out after one week of acclimation. The used apparatus consisted of a leucite box 20x20x20 cm size with black walls and a grilled floor. A platform 12 cm long and 7.5 cm wide was provided at the box entrance. This platform was lighted by a 40 W lamp at 50 cm distance, whereas the box was kept in the dark. The mouse was placed on the platform in front of the box entrance (4x3 cm) and the time taken by each animal to go into the box with all four paws was recorded (step through latency). When the animal was inside the box, the aperture was closed by an hand-operated sliding door and the mouse was given a 0.7 mA electric shock through the floor grills for 1 second. Then the animal was returned to its cage before being subjected to the test. During the test the same procedures of the training were used, except for the electric shock, which was omitted. The time between training and test was 72 hours for all the groups.

Post-training effects, due to drug administration, were studied subsequently. For this purpose, the different groups, each consisting of 10 mice of both strains, were administered intraperitoneally with the compounds of the invention immediately after the training.

The compounds were administered at different doses to evaluate the dose-effect relationship.

In order to exclude any influence of factors not connected with the learning on the results, some groups of mice of both strains were not subjected to the electric shock but were equally treated immediately after the training.

The administration of all of the compounds of the invention caused a statistically significant improvement on learning, the effect being related to the used dose, which ranged from 0.05 to 40 mg/kg. The improvement was observed on both strains, even though DBA mice proved to be more sensitive than C57 ones.

What above reported clearly shows that the derivatives of general formula 1 can conveniently be used as active principles of pharmaceutical compositions for the treatment of cerebropathies of dysmetabolic or toxic origin, of the cognition disorders connected with aging and of Parkinson's and Alzheimer's diseases.

Examples of said pharmaceutical compositions for the oral administration include capsules, pearls, tablets, granulates, powders, solutions, sachets, sustained-release forms, containing 5 to 500 mg of the active principle per unitary dose (as such or in form of the salts with hydrochloric, citric or tartaric acids), to be administered one or two times daily, according to the diagnosis and the patient's conditions.

For the parenteral administration, both intravenously and intramuscularly, suitable pharmaceutical forms are lyophilized vials or sterile solutions containing 2 to 300 mg of the active principle per unitary dose (as such or in form of the salts with hydrochloric, citric or tartaric acids), to be administered one or two times daily, according to the diagnosis and the patient's conditions.

The compositions of the invention can optionally contain other active principles having a complementary or useful activity.

Pseudophrynamine A can be obtained by extraction as well as by total synthesis, starting from tryptamine and tiglic acid, as reported in the following Scheme 1.

a) MeOH, conc. H₂SO₄, reflux, 7 hours; b) NBS, CCl₄ reflux, 4 hours; c) 3M NaOH, ClCOOMe, CH₃CN, rt 40 ' ; d) DMSO, conc. HCl, 0°C, 35' ; e) EtONa, EtOH, 0ºC, 30' ; 5+6, EtOH, rt 40' ; f) LiAlH₄, THF, reflux, 2 hours; g) (tBuOCO)₂O, Et₃N, CH₂Cl₂, rt 20 hours; h) Py₄Ag₂Cr₂O₇, CH₃CN, reflux, 2 hours; i) tBuOH, 2-methyl-2-butene, NaClO₂, NaH₂PO₄ , rt, 50 hours; j) 9, DOC, 4-pyrrolidinoρyridine, CH₂Cl₂, rt, 20 hours; 1) CF₃COOH, CH₂Cl₂, rt, 10' . Intermediates of formulae 8 and 9 are useful for the preparation of derivatives 1, by means of the conventional reactions for the preparation of esters, carbamates or N-methylated derivatives. In the following schemes, some of the synthetic pathways used for the preparation of compounds 1 are reported.

It will be understood that other methods, for examples based on different reagents, solvents, reaction conditions, protecting groups etc., can be used without departing from the spirit and scope of the invention.

The following examples illustrate furthermore the invention.

EXAMPLE 1

A solution of tiglic acid (60 g, 0.6 mol) in MeOH (85 ml) is treated with concentrated H₂SO₄ (12 ml) at room temperature and refluxed for about 7 hours. After that, the reaction mixture is diluted with water (20 ml) and repeatedly extracted with ether; the combined ether phases are washed with a sodium bicarbonate diluted solution and dried over sodium sulfate. Solvent is evaporated off under reduced pressure, to obtain 50.5 g of methyl tiglate (liquid) (74% yield), which will be used directly in the subsequent bromination reaction.

1H-NMR (200 MHz; CDCl₃): 1.7 ppm (m,3H,CH3); 1.8 ppm (m,3H,CH3); 3.7 ppm (s,3H,OMe); 6.6-7.0 (m,1H,CH).

EXAMPLE 2

A solution of methyl tiglate (50.5 g, 0.443 mol) in CCl₄ (300 ml) is treated, with stirring and under nitrogen atmosphere, with N-bromosuccinimide (NBS) (90 g, 0.506 mol) and refluxed for about 4 hours. Then precipitate is filtered and solvent is evaporated off under reduced pressure. The resulting oily residue is then distilled at about 16 mmHg (110-112ºC), to obtain 30 g of a mixture of bromoderivatives 5 and 6 in a 2:1 ratio.

¹H-NMR (200 MHz; CDCl₃) : 1.9 ppm (m,6H,CH₃ isomers 5+6); 3.75 ppm (s,3H,OCH₃ isomer 5); 3.8 ppm (s,3H,OCH₃ isomer 6); 4.05 ppm (d,2H,CH₂Br isomer 5); 4.25 ppm (s,2H,CH₂Br isomer 6); 6.95 ppm (tq,1H,CH isomer 5); 7.10 ppm (q,1H,CH isomer 6). EXAMPLE 3

A solution of tryptamine (30 g, 0.187 mol) in CH₃CN (200 ml) is treated with a 3M NaOH solution (187 ml, 0.561 mol) and the mixture is cooled to 0°C; then methyl chloroformate (28.8 ml, 0.376 mol) dissolved in CH₃CN (174 ml) is slowly added thereto. After about 40 min., 5% HCl (110 ml) is added to acid pH; phases are separated and the aqueous phase is extracted with CH₂Cl₂. After that, the combined organic phases are dried over sodium sulfate and evaporated under reduced pressure. The resulting oil is purified by crystallization from 2:1:1 EtOH:CH₂Cl₂:hexane, to obtain about 34.7 g of crystalline tryptamine methyl carbamate (85% yield); m.p. 78-79ºC.

1H-NMR (200 MHz; CDCl₃) : 3.00 ppm (t,2H,CH₂CH₂NH); 3.55 ppm (m,2H,CH₂CH₂NH); 3.70 ppm (s,3H,OMe); 4.75 ppm (broad s, 1H,NHCOOMe); 7.00 ppm (s,1H,NHCH); 7.15-7.60 ppm (m, 4H, aromatic); 8.10 ppm (broad s,1H,NHCH).

EXAMPLE 4

A solution of tryptamine methyl carbamate (12 g, 55 mmols) in DMSO (40 ml) is slowly treated with concentrated HCl (93 ml), under stirring and at 0°C. Then the reaction mixture is warmed to room temperature and it is left to react for about 20 min; after that it is diluted with water and extracted with ethyl acetate (8x200 ml) : the combined organic phases are washed with water to neutrality, dried over sodium sulfate and evaporated under reduced pressure. The resulting oil is crystallized from benzene, to give about 10 g of crystalline compound 7 (78% yield); m.p. 126-127°C.

¹H-NMR (200 MHz; CDCl₃) : 2.00-2.33 ppm (m,2H,CH₂CH₂NH); 3.30-3.60 ppm (m,3H,CH₂CH₂NH + COCH); 3.68 ppm (s,3H,OMe); 5.25 ppm (broad t, 1H, NHCOOMe); 6.90 ppm (d,1H,arom.); 7.10 ppm (t,1H,arom.); 7.20-7.40 ppm (m,2H,arom.); 8.30 ppm (s,1H,NHCO).

EXAMPLE 5

A solution of NaOEt (58.27 mmols) in EtOH (95 ml) at 0ºC and under nitrogen is treated with compound 7

(2.7 g, 11.65 mmols) dissolved in EtOH (70 ml) in about

30 min. After about 30 min., the mixture of bromoderivatives 5 + 6 (4.7 g, 24.47 mmols) dissolved in EtOH (11 ml) is added thereto, during 15 minutes, then the reaction mixture is warmed to room tempereture and it is left to react for about 40 min. After that, a

NH₄CI saturated solution is added, EtOH is evaporated off under reduced pressure, the aqueous phase is extracted with CH₂Cl₂ and the combined organic phases are dried over sodium sulfate and evaporated under reduced pressure. The resulting crude oil is subsequently purified by flash chromatography (7:3 EtOAc:hexane) to finally obtain 3.6 g of the 3-alkyl derivative (oil) (90% yield).

¹H-NMR (200 MHz; CDCl₃): 1.7 ppm (s, 3H,CH₃C=); 2.00-2.40 ppm (m,2H,CH₂CH₂NH); 2.68 ppm (d,2H,CH₂CH=); 2.80-3.15 ppm (m,2H,CH₂CH₂NH); 3.55 ppm (s,3H,OMe); 3.65 ppm (s,3H,OMe); 5.15 ppm (broad s, 1H,NHCOOMe); 6.50 ppm (t,1H,CH=C); 6.90-7.30 ppm (m,4H,arom.); 9.40 ppm (broad s,1H,NHCO).

EXAMPLE 6

The alkyl derivative obtained according to the procedure described in Example 5 (3.6 g, 10.4 mmols) is dissolved in anhydrous THF (100 ml) and added to a suspension of LiAlH₄ (1.97 g, 52 mmols) in anhydrous THF (206 ml) at 0°C, under nitrogen atmosphere. After 4 hour reflux, water (2.0 ml), 15% NaOH (2.0 ml) and water (4.0 ml) are added in this order, keeping the reaction mixture under strong stirring at room temperature for about 1.5 hours. After that, salts are filtered and repeatedly washed with CH₂Cl₂; then the filtrate is dried over sodium sulfate and evaporated under reduced pressure. The resulting residue is purified by flash chromatography (85:15 CH₂Cl₂:MeOH), to obtain 1.9 g of crystalline alcohol 8 (71% yield); m.p. 122-124ºC.

¹H-NMR (200 MHz; CDCl₃) : 1.62 ppm (s,3H,CH₃C=CH); 1.95 ppm (m,1H,HCHCH₂NCH₃); 2.15 ppm (m,1H,HCHCH₂NCH₃); 2.40 ppm (s;3H,CH₃N); 2.52 ppm (d,2H,CH₂CH=C); 2.54 ppm (m,1H,CH₂HCHNCH₃); 2.70 ppm (m,1H,CH₂HCHNCH₃); 3.55 ppm (broad s,1H); 3.92 ppm (s,2H,CH₂OH); 4.28 ppm (broad S,1H); 4.51 ppm (s,1H,NHCHNCH₃); 5.36 ppm (t,1H,CH=C); 6.58 ppm (d,1H,arom.); 6.76 ppm (t,1H,arom.); 7.04 ppm (t,2H,arom.).

EXAMPLE 7

A solution of compound 8 (1.8 g, 6.98 mmols) in anhydrous CH₂Cl₂ (100 ml), under nitrogen and at room temperature, is treated with Et₃N (1 ml), cooled to 0°C and then treated with (BOC)₂O (1.6 g, 7.33 mmols) dissolved in CH₂Cl₂ (30 ml). The reaction mixture is left to warm slowly to room temperature. After 12 hours the mixture is extracted with CH₂Cl₂, the organic phase is washed with a NaHCO₃ aqueous solution, dried over sodium sulfate and solvent is evaporated off under reduced pressure. The residue is then purified by flash chromatography (AcOEt) to obtain 1.93 g of compound 9 (oil) (78% yield).

¹Η-NMR (200 MHz; CDCl₃): 1.43 ppm (s,9H,tBu); 1.60 ppm s,3H,CH₃C=CH); 2.05-2.28 ppm (m,2H,CH₂CH₂NCH₃); 2.50- 2.80 ppm (m,7H,CH₂CH₂NCH₃ + CH₂CH=C + CH₃N); 3.88 ppm (s,2H,CH₂OH); 5.65 ppm (t,1H,CH=C); 7.25-7.40 ppm (m,2H,arom.); 7.64 ppm (d,1H,arom.); 8.06 ppm (broad s,1H,arom.).

EXAMPLE 8

A solution of compound 9 (0.97 g, 2.7 mmols) andPy₄Ag₂Cr₂O₇ (2.1 g; 2.8 mmols) in CH₃CN (27 ml) is refluxed for 2 hours. The resulting precipitate is filtered and repeatedly washed with CH₃CN and CH₂Cl₂; the filtrate is dried and evaporated under reduced pressure. The resulting residue is purified by flash chromatography (65:35 AcOEt:CH₂Cl₂) to give 682 mg of aldehyde 10 (oil) (71% yield).

¹H-NMR (200 MHz; CDCl₃): 1.39 ppm (s,9H,tBu); 1.57 ppm (s,3H,CH₃C=CH); 2.05-2.33 ppm (m,2H,CH₂CH₂NCH₃); 2.65- 3.00 ppm (m,7H,CH₂CH₂NCH₃ + CH₂CH=C + CH₃N); 5.90 ppm (t,1H,CH=C); 7.33 ppm (m,2H,arom.); 7.68 ppm (d,1H,arom.); 8.08 ppm (s,1H,arom.); 9.18 ppm (s,1H,CHO).

EXAMPLE 9

A solution obtained dissolving aldehyde 10 (682 mg, 1.92 mmols), 2-methyl-2-butene (1073 mg, 15.33 mmols) and tBuOH (7.66 ml) is added at 0°C to a solution of NaClO₂ (650 mg, 80%, 5.75 mmols), NaH₂PO₄ (793 mg; 5.75 mmols) and water (11.27 ml). After about 50 hours at room temperature, the reaction mixture is diluted with water and CH₂Cl₂, acidified with 5% HCl to pH 1, and extracted with CH₂Cl₂; then the aqueous phase is dried over sodium sulfate and solvent is evaporated off under reduced pressure. The resulting crude product is purified by flash chromatography (91:9 CH₂Cl₂:MeOH) to obtain 551 mg of acid 11 (77% yield); m.p. 68°C.

1H-NMR (200 MHz; CDCl₃): 1.40 ppm (s,9H,tBu); 1.75 ppm (s,3H,CH₃C=CH); 2.00-2.30 ppm (m, 2H,CH₂CH₂NCH₃) ; 2.60- 2.92 ppm (m,7H,CH₂CH₂NCH₃ + CH₂CH=C + CH₃N) ; 6.50 ppm (t,1H,CH=C); 6.92 ppm (d,1H,arom.); 7.10 ppm (t,1H,arom.); 7.20 ppm (m,2H,arom.); 8.67 ppm (S,1H,COOH).

EXAMPLE 10

A solution obtained dissolving alcohol 9 (173 mg, 0.483 mmol) and acid 11 (180 mg, 0.483 mmol) in anhydrous CH₂Cl₂ is treated, under nitrogen and at room temperature, with 4-pyrrolidinopyridine (20 mg, 0.135 mmol) and DCC (120 mg, 0.583 mmol). The reaction mixture is left to react at room temperature for about 20 hours, then DCC (60 mg, 0.583 mmol) and 4- pyrrolidinopyridine (10 mg, 0.068 mmol) are added again and stirring is maintained for 4 hours more. After that, the mixture, is diluted with CH₂Cl₂, washed with water, dried over sodium sulfate and solvent is evaporated off under reduced pressure. The resulting crude product is purified by flash chromatography (4:1 CH₂Cl₂: acetone) to obtain 250 mg of BOC-pseudophry- namine A 12 (oil) (73% yield).

1H-NMR (200 MHz; CDCl₃): 1.40 ppm (s,18H,tBu); 1.63 ppm

(s,3H,CH₃C=CH); 1.64 ppm (s,3H,CH₃C=CH); 1.90-2.40 ppm (m,4H,2CH₂CH₂NCH₃); 2.40-3.00 ppm (m,8H,2CH₂CH₂NCH₃ +

2CH₂CH=C); 2.65 ppm (broads,6H,2CH₃N); 4.10-4.40 ppm

(m,4H,2NHCHNCH₃ + CH₂OCO); 5.15 ppm (t,1H,CH=C); 6.35 ppm (t,1H,CH=C); 6.80-7.15 ppm (m,2H,arom.); 7.15-7.50 ppm (m,4H,arom.); 7.60 ppm (d,1H,arom.); 8.10 ppm (s,1H,arom.).

EXAMPLE 11

A solution of BOC-pseudophrynamine A 12 (200 mg,

0.281 mmol) in CH₂Cl₂ (4 ml) at 0ºC, under nitrogen, is added with CF₃COOH (2 ml). After 2 minutes only, the reaction is quenched with a NaHCO₃ aqueous solution to basic pH. The reaction mixture is extracted with

CH₂Cl₂, dried over sodium sulfate and solvent is evaporated off under reduced pressure. The resulting crude product is purified by flash chromatography (85:15 CH₂Cl₂:MeOH + 1% Et₃N) to obtain 137 mg of pseudophrynamine A 4 (95% yield).

1H-NMR (200 MHz; .CDCl₃): 1.60 ppm (s,3H,CH₃C=CH); 1.78 ppm (s,3H,CH₃C=CH); 1.95-2.10 ppm (m,4H,2CH₂CH₂NCH₃); 2.45 ppm (broad s,6H,2CH₃N); 2.50 ppm (d,2H,CH₂CH=C); 2.40-2.75 ppm (m, 6H,2CH₂CH₂NCH₃ + CH₂CH=C); 4.30 ppm (m,2H,2NHCHNCH₃); 4.47 ppm (s,2H,CH₂OCO); 5. 35 ppm (t,1H,CH=C); 6.55 ppm (dd,2H,arom.); 6. 68 ppm (t,1H,CH=C); 6.70 ppm (m,2H,arom.); 7. 02 ppm (m,4H,arom.).

EXAMPLE 12

A solution obtained dissolving BOC-alcohol 9 in anhydrous CH₂Cl₂ is treated with anhydrous pyridine (1.3 eq.) and the corresponding anhydride (RCO)₂O (1.2 eq.) (for R=C_nH_2n+1 with 1≤n≤7, CH(CH₃)₂, C(CH₃)₃, Ph), or acid chloride (1.2 eq.) (for R=CH₂Ph, CH₂CH₂Ph).

After about 12 hours at room temperature, the reaction mixture is diluted with water, extracted with CH₂Cl₂, dried over sodium sulfate and solvent is evaporated off under reduced pressure. Finally the corresponding BOC-esters are purified by flash chromatography. Yields range from 50% to 80%. Thereafter, BOC-esters are hydrolyzed with CF₃COOH, according to the procedure described in Example 11, obtaining yields from 60% to 75% (after flash chromatography).

1H-NMR (200 MHz; CDCl₃) of acetate 13 (oil):

1.60 ppm (s,3H,CH₃C=CH); 2.00 ppm (s,3H,CH₃CO); 1.90-

2.20 ppm (m,2H,CH₂CH₂NCH₃); 2.45 ppm (s;3H,CH₃N); 2.55 ppm (d,2H,CH₂CH=C); 2.70 ppm (m, 2H,CH₂CH₂NCH₃); 4.40 ppm

(s,3H,NHCHNCH₃ + CH₂OCO) ; 5.35 ppm (t,1H,CH=C); 6.60 ppm (d,1H,arom.); 6.75 ppm (t,1H,arom.); 7.05 ppm

(t,2H,arom.).

1H-NMR (200 MHz; CDCl₃) of phenyl ester 14 (oil):

1.61 ppm (s,3H,CH₃C=CH); 1.85-2.25 ppm

(m,2H,CH₂CH₂NCH₃); 2.50 ppm (s;3H,CH₃N); 2.60 ppm

(d,2H,CH₂CH=C); 2.70 ppm (m,2H,CH₂CH₂NCH₃); 4.40 ppm

(S,3H,NHCHNCH₃ + CH₂OCO); 5.35 ppm (t,1H,CH=C); 6.60 ppm

(d,1H,arom.); 6.75 ppm (t,1H,arom.); 7.05 ppm (t,2H,arom.); 7.30 ppm (m,5H,arom.).

¹H-N-MR (200 MHz; CDCI₃) of benzyl ester 15 (oil):

1.60 ppm (s,3H,CH₃C=CH); 1.85-2.25 ppm

(m,2H,CH₂CH₂NCH₃); 2.50 ppm (s;3H,CH₃N); 2.60 ppm (d,2H,CH₂CH=C); 2.70 ppm (m,2H,CH₂CH₂NCH₃); 4.40 ppm

(s,3H,NHCHNCH₃); 4.42 ppm (s, 2H,CH₂OCO); 5.25 ppm

(s,2H,CH₂Ph); 5.35 ppm (t,1H,CH=C); 6.60 ppm

(d,1H,arom.); 6.75 ppm (t,.1H,arom.); 7.05 ppm (t,2H,arom.); 7.30 ppm (m,5H,arom.). ¹H-NMR ( 200 MHz ; CDCl₃) of tert-butyl ester 16 (oil) :

1.40 ppm (s,9H,tBu); 1.62 ppm (s,3H,CH₃C=CH); 1.80-2.30 ppm (m,2H,CH₂CH₂NCH₃); 2.50 ppm (s;3H,CH₃N); 2.65 ppm (d,2H,CH₂CH=C); 2.72 ppm (m, 2H,CH₂CH₂NCH₃); 4.42 ppm (s,3H,NHCHNCH₃); 4.50 ppm (s,2H,CH₂OCO); 5.38 ppm (t,1H,CH=C); 6.60 ppm (d,1H,arom.); 6.70 ppm (t,1H,arom.); 7.10 ppm (t,2H,arom.).

EXAMPLE 13

A solution of alcohol 8 (2.5 g, 9.69 mmols) in CH₃CN (48 ml) is treated with a 37% formaldehyde aqueous solution (8.7 ml) and it is left to react for about one hour at room temperature. After that, NaBH₃CN (3 g; 48.5 mmols) and AcOH (1.76 ml) are added. The reaction mixture is left to react at room temperature for 2 hours, then more AcOH (1.76 ml) is added to the mixture, which is left to react for 2 hours more at room temperature, then is diluted with ethyl ether, washed with diluted sodium hydroxide and dried over sodium sulfate. Solvent is evaporated off under reduced pressure, the resulting crude product is purified by flash chromatography (9:1 CH₂Cl₂:MeOH) to give 1.84 g of the corresponding N-Me derivative (70% yield).

1H-NMR (200 MHz; CDCl₃) : 1.67 ppm (s, 3H,CH₃C=CH); 1.85- 2.35 ppm (m,2H,CH₂CH₂NCH₃); 2.50 ppm (s,3H,CH₃N); 2.52 ppm (d,2H,CH₂CH=C); 2.60 ppm (m,1H,CH₂HCHNCH₃); 2.75 ppm (m,1H,CH₂HCHNCH₃); 2.97 ppm (s,3H,CH₃N); 3.95 ppm (s,2H,CH₂OH); 4.23 ppm (s,1H,NCH₃CHNCH₃); 5.37 ppm (t, 1H,CH=C); 6.45 ppm (d,1H,arom.); 6.71 ppm (t,1H,arom:); 7.07 ppm (m,2H,arom).

EXAMPLE 14

A solution obtained dissolving the N-Me derivative obtained according to example 13 in anhydrous CH₂Cl₂ is treated with anhydrous pyridine (1.3 eq.) and the corresponding anhydride (RCO)₂O (1,2 eq.) (for R=C_nH_2n+1 with 1≤n≤7, CH(CH₃)₂, C(CH₃)₃, Ph), or acid chloride (1,2 eq.) (for R=CH₂Ph, CH₂CH₂Ph) are added thereto. After about 12 hours at room temperature, the reaction mixture is diluted with water, extracted with CH₂Cl₂, dried over sodium sulfate and solvent is evaporated off under reduced pressure. Finally the corresponding esters are purified by flash chromatography. Yields range from 60% to 85%.

1H-NMR (200 MHz; CDCl₃) of ester 17 (oil):

1.63 ppm (s,3H,CH₃C=CH); 2.05 ppm (s,3H,CH₃CO); 1.90- 2.20 ppm (m,2H,CH₂CH₂NCH₃); 2.45 ppm (s;3H,CH₃N); 2.53 ppm (d,2H,CH₂CH=C); 2.72 ppm (m,2H,CH₂CH₂NCH₃); 2.95 ppm (s;3H,CH₃N); 4.40.ppm (s,3H,NHCHNCH₃ + CH₂OCO); 5.38 ppm (t,1H,CH=C); 6.60 ppm (d,1H, arom.); 6.75 ppm (t,1H,arom.); 7.05 ppm (t,2H,arom.). ¹H-NMR ( 200 MHz ; CDCl₃ ) of ester 18 ( oil ) :

1.61 ppm (s,3H,CH₃C=CH); 1.85-2.25 ppm (m,2H,CH₂CH₂NCH₃); 2.52 ppm (s;3H,CH₃N); 2.61 ppm (d,2H,CH₂CH=C); 2.71 ppm (m,2H,CH₂CH₂NCH₃); 2.96 ppm (s;3H,NCH₃); 4.40 ppm (s, 3H,NHCHNCH₃) ; 4.42 ppm (s,2H,CH₂OCO); 5.25 ppm (s,2H,CH₂Ph); 5.38 ppm (t,1H,CH=C); 6.62 ppm (d,1H,arom.); 6.75 ppm (t,1H,arom.); 7.05 ppm (t,2H,arom.); 7.30 ppm (m,5H,arom.).

EXAMPLE 15

A solution obtained dissolving BOC-alcohol 9 in anhydrous benzene is treated with Et₃N and the corresponding alkyl- or aryl-isocyanate RNCO (1,2 eq.) (R=CH(CH₃)₂, C(CH₃)₃, Ph, mCl-Ph, CH₂Ph) dissolved in benzene. The reaction mixture is left to react at 0ºC under nitrogen for about 70-120 min., then solvent is directly evaporated off under reduced pressure and the corresponding BOC-carbamates are purified by flash chromatography. Yields range from 60% to 90%. Thereafter, BOC-carbamates are hydrolyzed with CF₃COOH according to the procedure described in Example 11, with yields from 65% to 75% (after flash chromatography). ¹H-NMR ( 200 MHz ; CDCl₃) of phenylcarbamate 19:

1.68 ppm (s,3H,CH₃C=CH); 1.98-2.08 ppm (m,1H,HCHCH₂NCH₃); 2.13-2.23 ppm (m,1H,HCHCH₂NCH₃); 2.48 ppm (s;3H,CH₃N); 2.56 ppm (d,2H,CH₂CH=C); 2.65 ppm

(m,1H,CH₂HCHNCH₃); 2.76 ppm (m,1H,CH₂HCHNCH₃); 4.52 ppm

(s,3H,NHCHNCH₃ + CH₂OCO); 5.46 ppm (t,1H,CH=C); 6.55 ppm

(d,1H,arom.); 6.75 ppm (t,1H,arom.); 7.02-7.14 ppm

(m,3H,arom.); 7.20 ppm (s,1H,CONH); 7.30-7.40 ppm (m,4H,arom.).

¹H-NMR ( 200 MHz ; CDCl3 ) of benzylcarbamate 20 :

1.67 ppm (s,3H,CH₃C=CH); 1.95-2.05 ppm

(m,1H,HCHCH₂NCH₃); 2.13-2.20 ppm (m, 1H,HCHCH₂NCH₃) ; 2.50 ppm (s;3H,CH₃N); 2.56 ppm (d,2H,CH₂CH=C); 2.63 ppm (m,1H,CH₂HCHNCH₃); 2.75 ppm (m,1H,CH₂HCHNCH₃); 4.52 ppm

(s,3H,NHCHNCH₃ + CH₂OCO) ; 5.25 ppm (s,2H,CH₂Ph); 5.43 ppm (t,1H,CH=C); 6.55 ppm (d,1H,arom.); 6.72 ppm

(t,1H,arom.); 7.00-7.15 ppm (m,3H,arom.); 7.20 ppm (s,1H,CONH); 7.30-7.40 ppm (m,4H, arom.). EXAMPLE 16

A solution obtained dissolving BOC-alcohol 9 (57 mg, 0.159 mmol) in anhydrous benzene (1 ml) is treated with trichloroacetyl isocyanate (23 μl; 0.191 mmol) dissolved in benzene (1 ml). The reaction mixture is left to react at 0°C under nitrogen, with stirring, for about 15 minutes, then the resulting solution is directly charged on a column containing Al₂O₃, eluting the product with a 3:1 AcOEt:Hexane mixture, then with MeOH. After that, the filtrate is evaporated under reduced pressure to obtain 44 mg of BOC-carbamate (69% yield), which is sufficiently pure to be hydrolyzed by CF₃COOH, according to the procedure reported in Example 12. 81 mg of carbamate 21 (59% yield) are obtained.

1H-NMR (200 MHz; CDCl₃): 1.60 ppm (s,3H,CH₃C=CH); 2.05 ppm (m,1H,HCHCH₂NCH₃); 2.20 ppm (m,1H,HCHCH₂NCH₃) ; 2.48 ppm (s;3H,CH₃N); 2.55 ppm (d,2H,CH₂CH=C); 2.62 ppm (m,1H,CH₂HCHNCH₃); 2.85 ppm (m,1H,CH₂HCHNCH₃); 4.40 ppm (s,2H,CH₂OCO); 4.56 ppm (s,1H,NHCHNCH₃); 5.00 ppm (s,2H,NH₂); 5.35 ppm (t,1H,CH=C); 6.62 ppm (d,1H,arom.); 6.76 ppm (t,1H,arom.); 7.05 ppm (m,2H,arom.).

EXAMPLE 17

A solution obtained dissolving BOC-alcohol 9 in anhydrous THF is treated with the corresponding imidazol-carbonylamine (1.2 eq) of general formula

and metal Na (2.0 eq.). The reaction mixture is left to react at room temperature, under nitrogen, for about 8-10 hours, then solvent is directly evaporated off under reduced pressure and the corresponding BOC- carbamates are purified by flash chromatography. Yields range from 60 to 90%.

Thereafter, BOC-carbamates are hydrolyzed with CF₃COOH according to the procedure described in Example 11, with yields ranging from 65 to 75%.

1H-NMR (200 MHz; CDCl₃) of n-hexyl-carbamate 22:

0.80 ppm (t,3H,CH₃); 1.30 ppm (broad s,6H,CH₂); 1.48 ppm (m,2H,CH₂CH₂NHCO); 1.60 ppm (s, 3H,CH₃C=CH); 2.05 ppm (m,1H,HCHCH₂NCH₃); 2.15 ppm (m,1H,HCHCH₂NCH₃); 2.45 ppm (s;3H,CH₃N); 2.55 ppm (d,2H,CH₂CH=C); 2.63 ppm (m,1H,CH₂HCHNCH₃); 2.73 ppm (m,1H,CH₂HCHNCH₃); 3.16 ppm (m,2H,CH₂NHCO); 4.35 ppm (s,3H,CH₂OCO + NHCHNCH₃); 4.70 ppm (broad s,1H,NH); 5.36 ppm (t,1H,CH=C); 6.60 ppm (d,1H,arom.); 6.75 ppm (t,1H,arom.); 7.01 ppm (m,2H,arom.). EXAMPLE 18

The N-Me derivative obtained according to Example 13 is reacted according to the procedure described in Examples 15, 16 and 17, to give the corresponding carbamates in yields ranging from 60% to 80% (after flash chromatography).

1H-NMR (200 MHz; CDCl₃) of carbamate 23:

1.66 ppm (s,3H,CH₃C=CH); 1.95-2.05 ppm

(m,1H,HCHCH₂NCH₃); 2.10-2.25 ppm (m,1H,HCHCH₂NCH₃); 2.46 ppm (s;3H,CH₃N); 2.56 ppm (d,2H,CH₂CH=C); 2.65 ppm (m,1H,CH₂HCHNCH₃); 2.74 ppm (m,1H,CH₂HCHNCH₃); 2.97 ppm (s;3H,NCH₃); 4.50 ppm (s,3H,NHCHNCH₃ + CH₂OCO); 5.45 ppm (t,1H,CH=C); 6.55 ppm (d,1H,arom.); 6.70 ppm (t,1H,arom.); 7.02-7.14 ppm (m,3H,arom.); 7.20 ppm (s,1H,CONH); 7.30-7.40 ppm (m,4H,arom.).

The other derivatives of general formula I, the preparation of which has not been described in the Examples, can be prepared analogously.

Claims

1. Compounds of general formula 1

wherein:

R is hydrogen or C₁-C₄ alkyl;

R₁ is selected from:

- hydrogen;

- a COR₂ group wherein R₂ is a straight or branched C₁- C₇ alkyl; phenyl optionally substituted by 1-3 halogen atoms, hydroxy, methoxy, methyl, trifluoromethyl, nitro, cyano groups; benzyl or phenethyl groups wherein the phenyl portion can be substituted as reported above;

- a CONHR₃ group wherein R₃ is hydrogen; straight or branched C₁-C₇ alkyl; phenyl optionally substituted as reported above; benzyl optionally substituted at the phenyl portion as reported above;

- a CONR^aR^b group wherein R^a and R^b, which are the same or different, are straight or branched C₁ -C₇ alkyl;

- a residue of formula:

wherein R is hydrogen or C₁-C₄ alkyl, with the proviso that when R₁ is said tricyclic residue, at least one of the two R groups is not hydrogen,

single enantiomeric forms, racemic mixtures, diastereoisomeric couples and pharmaceutically acceptable salts thereof.

2. Compounds according to claim 1, wherein R is hydrogen or methyl.

3. Compounds according to claim 1 or 2, wherein R¹ is hydrogen or a residue selected form the group consisting of :

-COCH₃; -COC₂H₅; -COC₃H₇; -COCH(CH₃)₂; -COC₄H₉;

-COCH₂CH(CH₃)₂; -COC₅H₁₁; -COC₆H₁₃; -COC₇H₁₅; -COC₈H₁₇; -COC₆H₅; -COCH₂C₆H₅; -COCH₂CH₂C₆H₅.

4. Compounds according to claims 1 or 2, wherein R¹ is a residue selected form the group consisting of :

-CONH₂; -CONHCH₃; -CONHC₂H₃; -CONHC₃H₇; -CONHCH(CH₃)₂; -CONHC₄H₉; -CONHCH₂CH(CH₃)₂; -CONHC₅H₁₁; -CONHC₆H₁₃;

-CONHC₇H₁₅; -CONHC₆H₅; -CONHC₆H₄Cl; -CONHCH₂C₆H₅;

-CON(CH₃)₂; -CON(C₂H₅)₂; -CON(C₃H₇)₂; -CON(C₄H₉)₂;

-CON(C₅H₁₁)₂; -CON(C₆H₁₃)₂; -CON(C₇H₁₅)₂.

5. A process for the preparation of the compounds of claim 1 or 2, which process consists in reacting comoound of formula 9

with suitable reagents, to obtain the corresponding primary alcohols, esters and urethanes thereof, finally removing any protecting groups present.

6. The use of compounds of claims 1 or 2 as therapeutic agents.

7. The use of pseudophrynamine A of formula 4

as a therapeutic agent.

8. Pharmaceutical compositions containing as the active principles the compounds of claims 1 to 4 or pseudophrynamine A.

9. The use of the compounds of claims 1, 2 and of pseudophrynamine A for the preparation of a medicament for the treatment of pathologies of Central Nervous

System.

10. The use of the compounds of claims 1, 2 and of pseudophrynamine A for the preparation of a medicament for the treatment of cerebropathies of dysmetabolic and/or toxic origin, of cognitive disorders connected with aging, of Parkinson's and Alzheimer's diseases.