MXPA95005234A - Abeo-ergoline derivatives as ligands of 5t - Google Patents

Abstract

Compounds of the formula (I) are provided wherein R 1 is a hydrogen atom, chlorine or bromine or a methyl, methylthio, hydroxy, cyano or carboxamido group, R 2 is an alkyl group of 1 to 3 carbon atoms or an allyl group; and R4 are independently a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, an alkenyl group of 3 to 5 carbon atoms, a cycloalkyl group of 5 to 6 carbon atoms alkyl of 1 to 3 carbon atoms, a phenylalkenyl group of 3 to 5) Carbon atoms to a phenyl group: groups which are optionally substituted by alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, trifluoromethyl, hydroxy or amino, or a group of the formula (a), wherein R6 is a hydrogen atom or an alkyl group of 1 to 3 carbon atoms and R7 is a phenyl group, a substituted phenyl group as described above or a heterocyclic ring, R5 is a hydrogen or bromine atom or an organic residue and R is H or an organic waste or a to pharmaceutically acceptable salt thereof. A method for their preparation and the pharmaceutical compositions containing them are also provided.

Description

"ABEO-ERGOLINE DERIVATIVES AS LIGANDS OF 5HT1A" Inventor (s): SERGIO MANTEGANI, Italian, domiciled in Via Cario Pisacane 57, 20129 Milan, Italy; TIZIANO BANDIERA, Italian, domiciled in C.so Vittorio Emanuele 44, 27025 Gam old (Pavia), Italy; ENZO BRAMBILLA, Italian, domiciled at Via P. Togliatti 41 / B, 22066 Mariano Comense (Como), Italy; CARLA CACCIA, Italian, domiciled in Via Torino 31, 21013 Gallarate (Várese), Italy and NICOLA CARFAGNA, Italian, domiciled in Via A. Terzaghi 41, 20014 Nerviano (Milan), Italy.

Causabiente: PHARMACIA S.P.A., Italian company, domiciled in Via Robert Koch 1.2, 20152 Milan, Italy ABEO-ERGOLINE DERIVATIVES AS LIGANDS OF 5HT1A This invention relates to new derivatives of 5- (10 - »- 9) abeo-ergoline, to the processes for their preparation, to their use as medicaments and to a pharmaceutical composition containing them. The novel compounds act on the central nervous system by binding to 5-HT receptors. and therefore can be used to manage or control the pathologies of the central nervous system. The novel compounds of this invention have the formula I wherein R. is a hydrogen, chlorine or bromine atom or a methyl, methylthio, hydroxy, cyano, carboxamido or nitro group; R2 is alkyl of 1 to 3 carbon atoms or an allyl group; R and R are independently a hydrogen atom, an alkyl group of 1 to 5 straight or branched carbon atoms, a linear or branched alkenyl group of 3 to 5 carbon atoms, a cycloalkyl group of 5 to 6 carbon atoms alkyl of 1 to 3 carbon atoms, a phenylalkyl group of 1 to 3 carbon atoms, a phenylalkenyl group of 3 to 5 carbon atoms or a phenyl group: groups which are optionally substituted by an alkyl group of 1 to 3 carbon atoms carbon, alkoxy of 1 to 3 carbon atoms, trifluoromethyl, hydroxy or amino: Rfi I 6 or a group of the formula -CR-, wherein R & is an OH atom of hydrogen or an alkyl group of 1 to 3 carbon atoms and R- is a phenyl group, a phenyl group substituted as described above or a heterocyclic ring having 5 or 6 members in the ring, which includes 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen: R, -, which may be in position 12, 13 or 14, is a hydrogen, bromine, fluorine or iodine atom, or a methoxy, cyano, carboxamido, nitro, methylthio or trifluoromethyl or a group of the formula NRgRg, wherein Rg and Rg are independently a hydrogen atom or an alkyl group of 1 to 3 carbon atoms, alkyl, acetyl, trifluoroacetal or methanesulfonyl. R is a hydrogen atom or an alkyl group of 1 to 5 straight or branched carbon atoms, a methanesulfonyl group, an acetyl group or a group of the formula -C (0) -NR "Rg where R" and Rg are as defined above. The dashed line represents the optional presence of a double bond at position 9-10 and / or 2-3. In the case where a bond is present in position 9-10, the compounds of the invention are of the formula I ' where R. R, 2, R ^, j. { and R ^ have the above meanings. The wavy lines () mean that the hydrogen atoms and the CHR ^ R group can be in the alpha or beta position with respect to the plane of the rings. In the case where a simple bond is present at position 2, 3, the compounds of the invention are of the formula I1 ' where, R, is hydrogen or a methyl group and R2,, R •, Re and R have the meanings mentioned above. The pharmaceutically acceptable salts of these abeo ergoline derivatives are included in the invention. In the definitions of R2, R ~, R, and R, alkyl groups of 1 to 3 carbon atoms and 1 to 5 carbon atoms are proposed to include the methyl, ethyl, n-propyl, i-propyl groups, butyl, i-butyl, cyclopropyl and methylcyclopropyl. In the definitions of R ~ and R, the phenyl-alkyl group of 1 to 3 carbon atoms comprises the benzyl and phenethyl groups; the phenylalkenyl group of 3 to 5 carbon atoms is proposed to include the phenyl-allyl group, phenyl-butenyl and phenylpropenyl. The heterocyclic ring which R- can represent, for example, a furanyl, imidazolyl, pyranyl, thienyl, pyrrolyl, pyrazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, orpholyl or thiopyranyl group. The most preferred compounds are those of the formula I ', wherein R represents a hydrogen atom or a cyano or carboxamido group, R represents a methyl group, R represents a hydrogen atom, R represents a group of the formula -CH (0H) Fen, R, represents a hydrogen, fluoro or iodo atom, or a methoxy, methyl ethyl, trifluoromethyl, carboxamido or nitro group, or a group of the formula RgRg., Wherein Rg and RQ are independently an atom of hydrogen or an alkyl group of 1 to 3 carbon atoms, acetyl, methanesulfonyl or trifluoroacetyl. The hydrogen at position 5 and the residue at position 8 are both in beta position. The present invention also provides a process for the production of the compounds of the formula I and their acid addition salts, the process comprising a) reacting a compound of the formula II wherein R 2, R and R 1 have the meanings given above, with a reducing agent such as sodium amalgam in ethanol, aluminum amalgam in aqueous THF (tetrahydrofuran), magnesium in methanol or ethanol at a temperature ranging from 0 ° C at 80 ° C. According to the present invention, the compounds of the formula II are prepared by the reaction of an alkaline salt of a compound of the formula III wherein R is as defined above, either with a compound of the formula RoY, where Ro has the meaning given above and Y is a leaving group such as an iodine or bromine atom, or a mesyloxy or tosyloxy group. or with a compound of the formula R, -C (0) -R7, wherein R, and R7 have the above meanings OP and, if desired, reacting an alkaline salt of the resulting compound, either with a compound of the formula RYY, wherein R, and Y are as previously defined, or with a compound of the formula R, C (0) R7, wherein R, and R7 have the meanings given above. Alkali salts can be obtained by reaction with strong base such as NaH, KH, ButLi or CHoLi in a solvent such as THF, HMPA (hexamethylphosphatriamide) or DME (dimethoxyethane) at a temperature ranging from -80 ° C to 0 ° C. The reactions for preparing a compound of formula II are usually carried out in an anhydrous solvent such as THF, HMPA or DME at a temperature ranging from -80 ° C to room temperature, for a period of 1 hour to 24 hours. A compound of the formula III can be prepared by reacting a compound of the formula IV wherein R2 is as defined above, with oxidizing agents such as hydrogen peroxide in solvents such as methanol, ethanol or acetic acid or with. peroxy acids such as m-chloroperbenzoic acid or peracetic acid in solvents such as DMF, ethanol or chloroform or with sodium periodate in aqueous THF. The compounds of the formula IV can be prepared either by reacting a compound of the formula V wherein R2 is as defined above, with (FenS), and (nBut) oP in a solvent such as dioxane, acetonitrile at reflux, or by reacting a compound of the formula (VI) wherein R2 and Y have the same meanings as before, with FenSNa in a solvent such as DMF, DMSO (dimethylsulfoxide) or HMPA at a temperature ranging from 80 ° C to 120 ° C. The compounds of formula III can also be prepared by reacting a compound of formula VI as defined above, with FenS02Na in a solvent such as HMPA or DMSO at a temperature ranging from 80CC to 140 ° C. The present invention also provides methods for converting a compound of the formula I into another compound of the formula I wherein one or more of the radicals of R, R, and R- have been altered. For example, a conversion can be carried out by reacting a compound of the formula I wherein R, and Rr are hydrogens, with a chlorinating agent such as N-Cl succinimide or sulfuryl chloride, or a brominating agent such as N-Br succinimide, in an inert solvent such as acetonitrile or chloroform; or with a thiomethylating agent such as methylsulfonyl chloride freshly prepared in a solvent such as THF or chloroform; or with an oxidizing agent such as N-Br succinimide in tert -butanol. The following compounds of the above methods of the formula I are provided, wherein R represents chlorine, bromine, a methylthio group and a hydroxy group. When R is a hydroxy group, the compounds of the formula I exist almost completely in the form of the tautomeric lactam. According to the present invention, a compound of the formula I, wherein R, is hydrogen, R2, R, R, and Re have the meanings mentioned above and R is hydrogen or an alkyl group of 1 to 5 carbon atoms linear or branched, it can be converted into a compound of the formula I'1, wherein R ,, R2, Ro, R ?, Rr, R have the meanings mentioned above, by treatment with zinc fine powder in concentrated hydrochloric acid or with a reducing agent such as sodium borohydride or cyano boron-sodium hydride in trifluoroacetic acid. The exploitation of general techniques such as fractional crystallization, or separation in column chromatography allows the separation in pure form of the C-3 diastereomers. According to the present invention, a compound of the formula I, wherein R is an acetyl, methanesulfonyl or dimethylaminocarbonyl can be obtained by the reaction of a compound of the formula I ", where R is hydrogen, with acetyl chloride , acetic anhydride, methanesulfonyl chloride or dimethylaminocarbonyl chloride in a solvent such as pyridine or ethyl acetate, while for R is an aminocarbonyl group, a carbamylation agent such as potassium cyanate in dilute hydrochloric acid is employed. According to the present invention, a compound of the formula I, wherein a double bond is present at the 2, 3 and R ^, R2, Ro, R ,, Rr position have the meanings mentioned above and R is hydrogen, can be converted into a compound wherein R is an alkyl group of 1 to 5 carbon atoms straight or branched by reaction with suitable alkyl iodide in the presence of sodium or potassium hydroxide milled in a solvent such as dimethyl sulfoxide. In addition, a compound of formula I, wherein R. is an "r" atom or a methylthio group and R is a hydrogen atom, can be converted to another compound of formula I, wherein R is a hydrogen atom or bromine atom or a methylthio group, and R, - represents a bromine atom or a methoxy, cyano or carboxamide group, by bromination in glacial acetic acid followed, if necessary, by the reaction of the compound resulting from the formula I. wherein R2, o and R1 are as defined above and R., is a hydrogen or bromine atom or a methylthio group, with the appropriate nucleophilic agent. The compounds of the formula I A. wherein R-1, A. represents a hydrogen atom, can be obtained from the corresponding compounds of the formula I., wherein R ,. it is a bromine atom or a methylthio group by careful reduction. The reduction can be carried out using cobalt or nickel hydride in methanol or ethanol.

For example, nucleophilic displacement by freshly prepared methoxide or sodium thiomethoxide in DMF or N-methyl-2-pyrrolidinone in the presence of a cuprous salt at 120 ° C converted a compound of formula I ', as defined above , in a compound of the formula I wherein R. is a methoxy or methylthio group. On the other hand, the reaction of a compound of the formula I with a cyanation agent, such as KCN / Cu2 (CN) 2 in DMF or N-methyl-2-pyrrolidine, and in the presence of cyano complexes a compound of the formula I, wherein Rc is a cyano group. A compound of the formula I, wherein R. is a carboxamide group can be prepared by reacting the compound of the formula I, wherein R.sup.r is a cyano group with hydrogen peroxide in methanol in the presence of a potassium or with KOH in tert-butanol at reflux or by heating in phosphoric acid. A compound of the formula I, wherein R, - is not a hydrogen or bromine atom and R, is a hydrogen atom can also be prepared by reduction of the corresponding compound of the formula I, where R. is a methylthio group or a bromine atom. The invention provides a method for converting a compound of the formula IR wherein R2, Ro, R, have the meanings mentioned above and Rr is hydrogen, in a compound of formula I, wherein a double bond is present at the 2, 3 and R position, is hydrogen and R2, Ro, R , have the meanings as defined above and Rr is a nitro, amino, dimethyl, diethylamino, acetylamino, or methanesulfonylamino group or a chlorine or iodine atom. The conversion is carried out by reacting the compound of the formula 1"with a nitrating agent such as acetyl nitrate or n-thiosulfate in a solvent such as acetic acid or sulfuric acid, to give in such a way the compound IR where R, is a nitro group. Careful reaction with Raney nickel in the presence of sodium hydroxide in ethanol as solvent gives a compound of formula I wherein a double bond is present at the 2, 3, R position, is hydrogen, R2, Ro, R, have the above mentioned meanings and Rr is an amino group and R is a hydrogen atom or conversely, compounds of this structure can be obtained by reaction of potassium t-butoxide in DMSO followed by reduction of the nitro group, by means of a reducing agent such as zinc fine powder, chloride is hollow in hydrochloric acid. Further reaction with suitable reagents such as methanesulfonyl chloride in a solvent such as pyridine gives a compound wherein R 1 - is an acetyl or methanesulfone group, while reaction with formaldehyde or acetaldeXdú in the presence of a reducing agent such as sodium anhydride in a solvent such as methanol or ethanol, provides the preparation of the compounds wherein R, - is a dimethyl or diethylamino group. Conversely, compounds may be obtained wherein R, - is a fluoro atom or an iodine atom, by reaction with a nitrosating agent such as sodium or potassium nitrite in a tetrafluoroboric acid or sulfuric acid in the presence of potassium periiodide.

Conversely, the compounds can be converted to where Rr is a bromine or iodine atom, in the compounds wherein Rr is a trifluoromethyl group by reaction with sodium trifluoroacetate in solvents such as hexamethylphosphatridene or -methyl pyrro-lidin-2. -one in the presence of iodide or cuprous bromide at 120-150 ° C. The starting compounds in formulas V and VI are known compounds (see GB1482871) or can be prepared by known reactions from known derivatives. The compounds of the formula I and their mu acid addition salts have a high affinity and are selective for the 5-HT-o-co-derivatives and show insignificant affinity towards the receptors at 1 f. "aj, alpha2, D1, D2. Therefore, the compounds provided by this invention can be used in the treatment of central nervous system (CNS) diseases such as anxiety, sleep and sexual disorders, psychoses, personality disorders, drug addiction, Impairment of memory associated with age, systemic trauma, Alzheimer's disease. For pharmaceutical use, the compounds of the formula I can be used as such or in the form of physiologically acceptable acid addition salts. Physiologically acceptable acids that can be used in salt formation include maleic, citric, tartaric, fumaric, methane sulfonic, acetic, benzoic, succinic, gluconic, lactic, malic, mucic, glutamic, ascorbic acids such as organic acids or hydrochloric, hydrobromic, sulfuric, or phosphoric as inorganic acids. Among the addition salts obtained at. employ hydrochloric, sufórico, methanesulfonic, citric and succinic acids, are most preferred. The compounds of this invention, or the pharmaceutically acceptable salts thereof, can be used in the manufacture of a medicament for use in the treatment of CNS diseases. Such a human or animal can be treated by a method comprising the administration thereto of a pharmaceutically effective amount of a compound of the formula (I) or salt thereof. In this way, the condition of the human or animal can be improved. The dose ratio can be a daily administration from 0.1 to 100 mg, more preferably from 1 to 25 mg, of active compound. As already mentioned above, the compounds of the formula I according to the present invention show interesting pharmacological properties, due to their activity in the sertotoiti-nérgicos receptors of the CNS of the subtype 5-HTj .. The biochemical and pharmacological profile of the compounds, which are the subject of the present invention, were estimated by evaluating their affinity for the 5-HT1A receptors.

Receptors Link Studies Receptor binding studies were carried out to determine the affinity of the test compounds of formula I.

Experiment 1: affinity for the serotonin 3 1A (5HT,.) Receptor [binding test for [H-8-Hydroxy-2-dipropyl-aminotetralin (3H-8-0H-DPTA)].

The preparation of the crude synaptosome fraction and the binding assay were conducted, according to the method reported in Journal of Neurochemistry, vol. 44, page 1685, 1985, by Hall et al. The frozen hippocampus, cut from rats, was homogenized in 40 volumes of 50 mM Tris-HCl cooled with ice (pH 7.4) and the suspension centrifuged at 500. g for 10 minutes at 0 ° C. The supernatant was centrifuged at 40,000 x g for 20 minutes at 0 ° C and the resulting pellet was homogenized in 40 volumes of the above buffer and incubated at 37 ° C for 10 minutes. After completion of the reaction, the suspension was centrifuged at 40,000 x g for 20 minutes at 0 ° C. The resulting pellet was washed twice by resuspension in 40 volumes of the above buffer and centrifugation, and finally suspended in 60 volumes of 50 mM Tris-HCl cooled with ice (pH 7.4) containing 1 mM manganese chloride to Use in the next trial. Aliquots (900 μl) of synaptosome membrane solution, 50 μl of 8-OH-DPAT solution treated with tritium at the terminal concentration of 0.2 nM and 50 μl of the test compound solution or 50 μl of solution were added to the aliquots. its medium, and incubated at 37 ° C during minutes. Then 5 ml of ice-cold 50 mM Tris-HCl buffer was added to the mixture (pH 7.4), was rapidly filtered under vacuum through Whatman 6Fi ti filters and washed twice with 5 ml of the same buffer. The radioactivity of the remaining residue in the filters was measured by the liquid cente-lio counter. The specific binding was not determined under the presence of 10 M serotonin (5-HT). The 50% inhibition concentration (CIr) of the test compound was determined graphically. The results are summarized in the Table.

Experiment 2: affinity for the serotonin receptor 2 (5-HT2) (H-ketanserin binding test).

The preparation of the crude synaptosome fraction and the binding assay were conducted according to the method reported in Molecular Pharmacology, vol. 21, page 301 1981 by Leysen et al. The frozen cerebral cortex, cut from r to t, was homogenized in 30 volumes of 0.32 M sucrose solution cooled with ice and the suspension was centrifuged at 1000 x g for 10 minutes at 0 ° C. The supernatant was centrifuged at 40,000 xg for 20 minutes at 0 ° C and the resulting pellets were homogenized in 30 volumes of ice-cold 50 mM Tris-HCl buffer (pH 7.7) and incubated at 37 ° C for 10 minutes. minutes The suspension was centrifuged at 40,000 x g for 20 minutes at 0 ° C again. The resulting pellet was homogenized in 100 volumes of the above buffer and provided as a synaptosome membrane solution for the next assay.

Aliquots (900 μ) of synaptosome membrane solution, 50 μl of H-Cetanserin solution to the final concentration of 0.2 mM and 50 μl of the test compound or its medium were added and incubated at 37 ° C for 20 minutes. After completion of the reaction, the mixture was rapidly filtered under vacuum p through Watman GF / B filters. The filters were washed 3 times with 5 ml of the above buffer, and then the radioactivity of the remaining residue in l ° s filters was measured by the liquid scintillation counter. The specific binding was not determined under the presence of 10, μM of mianserin. The 50% inhibition concentration (Cl,. ") Of the test compound was determined graphically. The results are summarized in the Table.

Ex-effect 3: affinity for the dopamine 2 receptor (D2) (H-Espiperone binding test).

The preparation of the crude synaptosome fraction and the binding assays were conducted according to the method reported in the European Journal of Pharmacology, vol 46, page 377, 1977 by I. Créese et al. The frozen chilled body, cut from rats, was homogenized in 100 volumes of 50 mM Tris-HCl cooled buffer with ice (pH 7.7) and suspension was centrifuged at 500 x g for 10 minutes at 0 ° C. The supernatant was centrifuged at 50,000 x g for 15 minutes at 0 ° C and the resulting pellet was homogenized in 100 volumes of the above buffer and then the suspension was centrifuged at 50,000 x g for 15 minutes at 0o again. The resulting pellet was homogenized in 150 buffer volumes of 50 mM Tris-HCl (pH 7.1) containing potassium chloride in 120 mM, 2 mM calcium chloride, 1 mM magnesium chloride, 0.1% ascorbic acid and 10 μM pargyline. . The suspension was incubated at 37 ° C for 10 minutes and then provided as a synaptosome membrane solution for the following assays. Aliquots (900 μ) of synaptosome membrane solution, 50 μl of solution were added to the aliquots. 3 H-spiperone at the terminal concentration of 0.2 nM and 50 μl of the test compound solution or 50 μl of its medium, and incubated at 37 ° C for 20 minutes.

After the completion of the reaction, the mixture was rapidly filtered through vacuum through Whatman filters.

GF / B The filters were washed three times with 5 ml of the above buffer, and then the radioactivity of the remaining residue in the filters was measured by the liquid scintillation counter. The specific binding was not determined under the presence of 100 juM of (L) -Sulpiride. The concentration at 50 2 (Cl 50) of the test compound was determined graphically, the results are summarized in the Table.

Table Link Profile Cl 50 nM Example D, D, 5-HT 1A 5-HT, 3 1850 940 6 110 4 1920 620 330 1000 2540 850 800 800 33 > 10000 > 10000 6 > 10000 34 > 10000 5000 100 > 10000 > 10000 6030 530 > 10000 36 > 10000 4480 100 > 10000 39 7100 130 6 2080 40 2750 4870 3 1240 42 > 10000 2000 18 1860 In therapeutic use, the active compounds can be administered orally, rectally, parenterally or topically, preferably orally. Thus, the therapeutic compositions of the present invention can take the form any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration. Compositions for oral administration are the preferred compositions of the invention and these are the known dosage forms for such administration, for example, capsule tablets, syrups and aqueous or oily suspensions. The excipients used in the preparation of these compositions are the excipients known in the pharmacy art. The tablets can be prepared by mixing the active compound, with inert diluent, such as calcium phosphate, in the presence of disintegrating agents, for example, magnesium stearate, and tabletting the mixture by known methods. Such tablets, if desired, can be provided with enteric coatings by the known methods, for example, by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules containing the active compound with or without added excipients, can be prepared by conventional means and, if desired, can be provided with enteric coatings in a known manner. Tablets and capsules may conveniently contain 2 to 10 mg of the active compound each. Other compositions for orai administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as carboxymethylcellulose sodium, and oily suspensions containing a compound of the invention. present invention in a suitable vegetable oil, for example, arachidic (peanut) oil. The compositions of the invention suitable for rectal administration are the known pharmaceutical forms, for administration, for example, suppositories with cocoa butter or polyethylene glycol bases. The compositions of the appropriate version for parenteral admi nination are pharmaceutical forms! known for such administration, for example, sterile suspensions or sterile solutions in a suitable solvent. In some formulations, it may be beneficial to use the compounds of the present invention in the form of very small particles, for example, as obtained by milling with fluid energy. The following examples illustrate the invention. The following reaction scheme illustrates the invention. twenty Example of formulating the pharmaceutical composition of tablets: i Tablets containing 10 mg of a compound of the formula I can be prepared by the following composition.

Compound of example 33 10. 0 mg Lactose 60 mg Corn starch 25 mg Crystalline cellulose 20 mg Polyvinylpyrrolidone KOQ 2 mg Talc 4 mg Magnesium stearate 0.5 mg The active compound is sprayed with an atomizer to make a fine powder having an average particle size below 10 μ. The fine powder of the active compound, lactose, corn starch and crystalline cellulose are mixed thoroughly with a kneader and then kneaded with an agglutinating paste prepared by the polyvinylpyrrolidone K-. The wet mass is passed through a 200 mesh screen and then dried in an oven at 50 ° C. The dry granule containing 3 to 4% water content is passed through a 24 mesh screen. The magnesium stearate and talc are mixed and tablets are compressed by using a rotary tablet machine , with a punch diameter of 8 mm. Some of the preferred compounds of the present invention are listed below: 5Beta 10- * 9) abeo-9, 10-Dideshi dro-6-methyl-8-beta-methyl-1-ergoline 5alpha (10? 9) abeo-9, 10-Didehydro-6-methyl-8-beta-methyl-ergoline Beta (10? 9) abeo-9, 10-Didehydro-6-met il-8alpha-methyl-ergoline Beta (10? 9) abeo-6-methyl-8-Beta-methyl-10alpha-ergoline 5Beta (10- »9) abeo-9,10-Didehydro-2-cyano-6-methyl-8-beta-methyl-ergoline 5Beta (10 -Jr 9) abeo-9, 10-Didehydro-2-a m i w ocarbonyl-6-met i l -8 Beta-methyl-ergoline- 5Beta (10- * 9) abeo-9,10-Didehydro-6-methyl-8Beta- (3-phenyl) propyl-ergoline 5Beta (10- ^ 9) abeo-9, 10-Di dehydro-2-bromo-6 -meti l-8Beta-methyl-ergoline 5Beta (10 -? '9) abeo-2,3Beta-dihydro-9, 10-didehydro-l-amino-carbonyl-6-methyl-8-beta-methyl-ergoline 5Beta (10-79) abeo-2,3Beta-dihydro-9,10-didehydro-l-methanesulfonyl-6-methyl-8Beta-methyl-ergoline 5Beta (10? 9) abeo-9, 10-didehydro-6-methyl-8Beta-methyl-12-bromoergoline SBetaflO- ^ gíabeo-g, 10-didehydro-6-methyl-8alpha-methyl-12-bromoergoline 5Beta (10- * 9) abeo-9,10-didehydro-6-methyl-8-beta-methyl-13-bromoergoline 5Beta (10- * 9) abeo-9,10-didehydro-6-methyl-8Beta-methyl-12-cyanoergoline 5Beta (10-> 9) abeo-9,10-didehydro-6-methyl-8-beta-methyl-12-aminocarbonyl-ergoline 5Beta (10-9'9) abeo-9, 10-didehydro-6-methyl-8Beta-methyl-3-mertylthio-ergoline Beta (10- ^ 9) abeo-9, 10-dideshi dro-6-methyl-8-beta-methyl-12-methoxy-ergoline 5Beta (10- * 9) abeo-9, 10-didehydro-6-methyl-8-beta-methyl-13-methoxy-ergoline 5Beta (10-?> 9) abeo-6-methyl-8-methyl-8-beta-methyl-12-methoxy-10-beta-ergoline 5Beta (10-'9) abeo-9, 10-Di of shi d r or 6-meti 1-SBeta-meti 1-12-nitro-ergoline 5Beta (10- »9) abeo-9,10-Didehydro-6-methyl-8-beta-methyl-12-amino-ergoline 5Beta (10- * 9) abeo-9, 10-Didehydro-6-methyl-8Beta-methyl-12-me years ulf oni lamino-erg or lina 5Beta (10- * 9) abeo-9, 10-Didehydro-6-methyl-8-beta-methyl-13-methanesulfonylamino-ergoline SBetaílO- ^ abeo-g.lO-Dideshidro-ó-methyl-dBeta-methyl-12-f luoro-ergoline 5Beta (10- "> 9) abeo-9, 10-Didehydro-6-methyl-8-Beta-methyl- 13-fluoro-ergoline 5Beta (10- »9) abeo-6-methyl-8Beta-methyl-l 2-fluoro-l-Beta-ergoline 5Beta (10- * 9) abeo-2,3Beta-Dihydro-9, 10-didehydro-6-methyl-8Beta-methyl-12-fluoro-ergoline 5Beta (10- * 9) abeo-2,3Beta-Dihydro-9,10-dihydro-6-methyl-8Beta-methyl-12-rlluoromethyl-ergoline 5Beta (10 - * 9) abeo-6-me? L-8 Beta-me il-12-fluoro-lOalpha-ergoline 5Beta (10- * 9) abeo-6-me i l-8-Beta-methyl-12-aminocarbonyl-lOalpha-ergoline 5Beta (10- * 9) abeo-9, 10-Didehydro-6-methyl-8-Beta-me-12-iodo-ergoline 5Beta (10- * 9) abeo-9,10-Didehydro-6-methyl-8-beta-methyl-12-trifluoromethyl-ergoline 5Beta (10-f »9) abeo-6-methyl-8Beta-methyl-12-tri-lurome il-lOalpha-ergoline 5Beta (10- * 9) abeo-6-methyl-8Beta-methyl-l 2-trifluoromethyl-l-Beta-ergoline Example 1 5Beta (10? 9) abeo-9, 1Q-D1 dehydro-6-methyl-8-Beta-phenyl-thiomethyl-ergoline.

A solution of 22.6 g of 5 (10- * 9) abeo-9, 10-didehydro-6-methyl-8-beta-hydroxymethyl-ergoline and 21 g of diphenyldisulfide and 20 g of tri-n-butylphosphyl was heated to reflux. Na in 200 ml of acetonitrile, for 2 hours. The solvent was completely evaporated and the oily residue was chromatographed on silica gel eluting with cyclohexane / ethyl acetate 1/1, to give after crystallization with diethyl ether, 29 g of the title compound, m.p. 147-151 ° C.

Example 2 5Beta (10? 9) abeo-, 10-Di dehydro-6-me ti-8-Beta- (phenylsulfonyl) methyl-ergoline.

Portion by portion was added to a solution of 3.6 g of 5Beta (10? 9) abeo-9, 10-didehydro-methyl-8-beta-phenylthiomethyl-1-ergoline in 50 ml of methanol and 5 ml of methanesulfonic acid, 3.5 g of m-chloroperbenzoic acid (50%), at room temperature. After stirring for 2 hours, the solvent was removed and the residue was taken up in ethyl acetate and washed with a saturated sodium hydrogen carbonate solution. After washing with brine and dried, the solvent was removed and the crude reaction mixture was filtered on a small pad of silica gel eluting with cyclohexane / ethyl acetate 2/1. Crystallization with diethyl ether yielded 2.1 g of the title compound, m.p. 163-165 ° C.

Example 3 5Beta (10 9) abeo-9, 10-Didehydro-6-methyl-8-beta-methyl-ergoline.

A mixture of 11.8 g of SBetailO-9) -abeo-9, 10-didehydro-6-methyl-8-Beta- (phenylsulfonyl) methyl ergoline and 2.2 g of metallic magnesium and a few crystals of mercury chloride in 200 ml were stirred. of dry ethanol, for 2 hours at room temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and dilute ammonium hydroxide. After washing with brine and drying, the concentration gave 5.8 g of the title compound as bright crystals, m.p. 218-220 ° C.

Example 4 5Beta (10- »'9) abeo-9, 10-Didehydro-2-bromo-6-methyl-8-beta-methyl-ergoline.

Portion by portion was aggravated to a solution of 2.5 g of 5Beta (10? 9) abeo-9, 10-dydrohydro-6-methyl-8-methyl-ergoline in 7.5 ml of dioxane, 1.9 g of N-bromo-succinimide. After stirring at 40 ° C for 2 hours, the solvent was removed and the residue chromatographed on silica gel eluting with cyclohexane / acetone, 2/1. After crystallization with ethyl acetate, 1.3 g of the title compound, m.p. 78-80 ° C.

Example 5 5Beta (10-y9) abeo-9,10-Didehydro-2-methylthio-6-methyl-8-beta-methyl-ergoline.

A freshly prepared solution of 5 g of methylsulfonyl chloride in 100 ml of methylene chloride was slowly added dropwise to a stirred solution of 11.9 g of 5Beta (10? 9) abeo-9,10- didehydro-6-ethyl-8-beta-methyl-ergoline in 300 ml of methylene chloride at -20 ° C. After stirring for 1 hour at -20 ° C, the yellow solution was left at room temperature for 1 hour. After division with a dilute ammonium hydrogen solution, the organic phase was dried and the organic phase was evaporated. The residue was crystallized with a 2/1 cyclohexane / acetone mixture to give 11.7 g of the title compound, m.p. 77-79 ° C.

Example 6 5Beta (10-9) abeo-9,10-Didehydro-6-methyl-8Beta- (2-phenyl) -ethyl-ergoline They were added to a solution of 3 g of 5Beta (10- * 9) abeo-6-methyl-8Beta- (phenylsulfonyl) methyl-ergoline in 75 ml of tetrahydrofuran at -78 ° C, 9.17 ml of n-butyl lithium 2.5 M in hexane. After one hour at -78 ° C, a solution of 1.8 g of benzyl bromide in L0 ml of tetrahydrofuran was slowly added and stirring was continued at -78 ° C for 1 hour, then left for 2 hours at room temperature. ambient. The reaction mixture was diluted with an aqueous, saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, concentrated by evaporation and subjected to chromatography on silica gel eluting with 1: 1 hexane / acetone or ethyl 3/1 to yield 2.7 g of a mixture of di- sulfone, which was treated with 0.38 g of metallic magnesium and a few crystals of mercury chloride in 50 ml of dry ethanol for 3 hours at room temperature. The solvent was evaporated thoroughly and the crude reaction mixture was taken up in ethyl acetate, washed with brine and dried. After chromatography on a small pad of silica gel eluting with cyclohexane / ethyl acetate, 4/1 and the additional crystallization with ether and water, 1.8 g of the title compound were obtained in a yield 76%, pf 112-115 ° C.

Ej emp 1 or 7 5Beta (10- »9) abeo-9,10-Didehydro-6-methyl-1 -8Beta- (4-buten) -1 -i 1 -gol By working as in Example 6, but using allyl bromide in place of benzyl bromide, the title compound was obtained in a 45% yield, m.p. 87-90 ° C.

Example 8 5Beta (10- * 9) abeo-9,10-Didehydro-6-methyl-8-Beta- (3-pheny1) propi 1-ergol i na Operating as in Example 6, but using ethyl bromide in place of benzyl bromide, the title compound was obtained in a yield of 55%, m.p. 107-109 ° C Example 9 5Beta (10 9) abeo-9, 10-Di deshi dro-6-met i 1 -8 Beta-hexy 1- 1 -i 1 -green By working as in example 6, but using rv ^ pentyl bromide instead of benzyl bromide, the title compound was obtained in a yield of 35%, m.p.

Example 10 Beta (lQ-9) abeo-9, 1 Q-Di deshi dro-6-met i-8-Beta-2- (3,4-dimethoxy-phenyl) ethyl-ergoline By working as in Example 6, but using bromide of 3, -d i met oxy-benzyl, the title compound was obtained in a yield of 40%, m.p. 121-122 ° C.

Example 11 5Beta (10- »9) abeo-9, 10-Di deshi dro-6-met i 1 -8 Beta- (2-cyclohexy 1) -eti 1-ergol ina Operating as in Example 6, but using clohexyl bromide lmethyl in the case of bromide debencyl, the title compound was obtained in a yield of 20%, m.p. 88-90 ° C.

Example 12 5Beta (10-9) abeo-9, 10-Di deshi-2-bromo-6-met i 1-8Beta- (2-phenyl) ethyl-ergoline Operand as in Example 4, but using 5Beta (10-) 9) abeo-9, 10-di deshi dro-6-me i 1 -8Be a- (2-phen i 1) -et i 1 -ergol i na instead of 5 Beta (10 - * 9) abeo-9, 10-di deshi dro-6-met i 1 -8 Beta-met i 1-ergo 1 i na, the title compound was obtained in 65% yield, mp. 106-108 ° C.

Example 13 5Beta (10- »9) abeo-9, 10-Di deshi dro-6-met i-8-Beta- (2-methyl) propyl-ergoline Operating as in Example 6, but using isopropyl iodide in place of benzyl bromide, the title compound was obtained in a yield of 22%, m.p. 118-120 ° C.

Example 14 5Beta (I0- * 9) abeo-9, 10-D deshi d ro-2-ci ano-6-met i 1 -8 Beta-met i 1 -ergol i na A stirred solution of 4 g of 5Beta- (10? 9) abeo-9, lOdi deshi dro-6-met i-8-Beta-methyl-1-ferrogol in 200 ml of acetoni, a solution of 2.6 g isocyanate of c 1 orosul foni 1 or in 20 ml of acetonitrile at room temperature. After stirring for 80 hours, 8 ml of triethylamine was added at 0 ° C. The solution was left at 0 ° C for 3 hours, then treated with a saturated solution of sodium carbonate and extracted with ethyl acetate. The organic phase was washed with brine, se. dried and concentrated to a small volume to provide 2.8 g of the title compound, m.p. 253? 255 ° C.

Example 15 5Beta (10-y9) abeo-9, 10-Di deshi dro-2-am i nocar boni 1-6-meti 1-8 Beta-me il-ergoline It is a < »Resaron a solution of 5beta (10" ^ 9) - abeo-9, 10-dideshidro -2-ci ano-6-met i-8beta-ergoline and 1.5 <liter of potassium carbonate in 50 ml of ethanol and 10 ml of water, 1.5 ml of hydrogen peroxide (120 volumes) at room temperature After 3 hours, the solution was concentrated and partitioned between ethyl acetate and brine, after drying and evaporation of the solvent, the residue was crystallized from acetone to yield 0.6 g of the title compound, mp 270-273 ° C.

Example 16 5Beta (lQ-9) abeo-9, 1 Q-ideshidro -6-methyl-8beta-2 (2-f uri 1) et i 1 ergoline.

By working as in Example 6, but using 2-furyl chloride instead of benzyl bromide, the title compound was obtained in a yield of 30%, m.p. 100-103 ° C.

Example 17 SBeta-QO- 9) abeo-9, 10-didehydro-6-n-propyl-8be a-met i 1-ergol i na.

Operating as in Example 3, but employing 5beta- (10-99) abeo-9, 10-didehydro-6-n-propyl-8beta- (f eni 1 sulf or -n-1) meth i 1 -gol , instead of 5beta (10 - * • 9) abeo-9, 10-didehydro-6-met i-8beta-Cphenylsul fonyl) methyl-ergo-lino, the title compound was obtained in a yield of 35% , pf 176-178 ° C.

Example 18 5Beta (10- »9) abeo-9, l-didehydro-6-methyl-1 -8beta- (2-hydroxy-2-phenyl-1) eti 1-ergol ina.

Operating as in Example 6, but using benzaldehyde in place of benzyl bromide, the title compound was obtained in a 15% yield as a mixture of d and astereomers.

Example 19 5Beta (10- ^ 9) abeo-9, 10-d ideshidro -6-met i 1 -8be ta- (2-met i 1 -2-hydroxy) propi 1-ergoline.

Operating as in Example 6, but using acetone in place of benzyl bromide, the title compound was obtained in a yield of 20% m.p. 92-94 ° C.

Example 20 5Beta (10-? 9) abeo-9, 10-d ideshydro -2, 13-di bromo-6-methy1-8 be t-methyl ergoline They were added to a solution of 10 g of 5beta- (10- * " 9) abeo-9, 10-didehydro-6-met i-8beta-methyl-ergoline in 100 ml of glacial acetic acid, slowly, at room temperature, 15 g of bromine dissolved in 50 ml of glacial acetic acid. After 2 hours of stirring at room temperature, the resulting reaction mixture was concentrated and diluted with chloroform and subsequently partitioned with an ammonium hydroxide solution.The organic phase was dried, then the solvent was completely removed. Ethanol to provide 14.3 g of the title compound, mp 132-135 ° C.

Example 21 5Beta- (10-? 9) abeo-9, 10-Didehydro-6-methyl-8beta-methyl 1-13-bromo-ergoline.

They were added slowly in portions, at 0 ° C, to a solution of 5 g of 5beta (10- * 9) abeo-9, 10-di-dehydro-2, 13-di bromo-6-methyl-8-beta 1 i-ol ol and 12 g of cobalt dichloride hexahydrate in 10 ml of methanol, 7 g of sodium borohydride. The black mixture was stirred for 15 minutes. The precipitate was then filtered through celite and washed with methanol. The reaction mixture was concentrated and partitioned between chloroform and a concentrated solution of ammonium hydroxide. After drying, the solvent was taken and the residue was chromatographed on silica gel eluting with cyclohexane / ethyl acetate 3/1. The fractions containing the product were accumulated and the solvent was removed. After crystallization with isopropanol, 2.7 g of the title compound, m.p. 121-124 ° C.

Example 22 5Beta (10 - »9) -abeo-9,, 10-didesh idro -2-thiomethyl-6-met: 11 - 8beta-meti 1 -12-bromo- -ergo 1 i na and 5beta (10 ~ r9) abeo - • 9, 10-d ideshidro * - 2 -ti omet i 1- -6-met i 1-í 8beta-met i 1 - -13-b romo- • er go-lina Operating as in Example 20, but using 5beta (10- ^ 9) abeo-9, 10-d ideshidro -2-ti orneti 1-6-methyl-1-beta-1-ergol i na instead of 5beta ( 10 - -> 9) abeo-9, 10-d ideshidro -6-pet i-8beta-meti 1-er goal after careful separation with column chromatography, the 5beta was isolated (10 - * " 9) abeo-9, 10-dideshidro -2-ti omet i 1 -6-meti l-8beta-meti 1 -13-bromo-ergol i na in a yield of 45%, mp 106-108 ° C plus the 5beta (10 - * - 9) abeo-9, 10-d ideshidro -2-ti omet i 1-6-meti l-8beta-meti 1-12-brorao-ergoline isolated in a yield of 12%, mp 121- 123 ° C. Example 23 Beta-dQ-* -9) abeo-9, 10-didehydro-6-met i 1 -8beta-meti 1-12-bromo-ergoline.

Operating as in Example 21, but employing 5beta (10 - * 9) abeo-9, 10-didehydro-2-methyl thio-6-methylo-8beta-met i 1-12-bromo-ergol i na instead of 5beta (10 - ^ 9) -abeo-9, 10-d ideshidro »-2, 13-di bromo-6-met i 1-8 beta-rae ti 1-ergoline and nickel clouro hexahydrate instead of hexahydrate Cobalt chloride, the title compound was obtained in a yield of 25%, mp 136-137 ° C.

Example 24 5Beta (10- ^ 9) abeo-9, 10-d ideshydro -6-methy1 -8bet a-rae t i 1- 12-methoxy-ergoline.

They were added to a solution of 3 g of 5beta- (10-J !!, '9) abeo-9, 10-didehydro-6-met i l-8beta-raetyl-12-bromo ergoline in 70 ml of dimethylformamide , nitrogen, 3 g of cuprous iodide and 2 g of sodium methoxide, prepared, dried. The resulting mixture was stirred at 120 ° C for 4 hours, then diluted with a concentrated solution of ammonium hydroxide and extracted with ethyl acetate. The organic phase was washed with brine, dried and evaporated. The residue was chromatographed on silica gel eluting with cyclohexane / ethyl acetate, 5/2, to provide 1.2 g of the title compound, m.p. 115-116 ° C.

Example 25 5Beta (10- "9) abeo-9, 10-dideshidrs -6-met i l-8beta-met i 1-12-cyano-ergoline.

By working as in Example 24, but using potassium cyanide instead of sodium methoxide and cuprous cyanide instead of cuprous iodide, the title compound was obtained in a yield of 30, m.p. 102-105 ° C.

Example 26 5Beta (10"^ 9) abeo-9, 10-d ideshydro-2-t i omet i 1-6-met i 1- 8beta-meti 1, -13-methoxy-ergoline.

Operating as in Example 24, but using 5beta- (10 ^^ 9) abeo-9, 10-d ideshidro -2-thiome i 1-6 -methyl 1-8beta-met i 1-13-bromo-ergol i Na instead of 5beta (10 ~ * 9) -abeo-9, 10-d ideshidro -6-meti l-8beta-meti 1-12-bromo-ergoli-na, the title compound was obtained in a yield of 35%. %, pf 124-127 ° C.

Example 27 SBeta-QO- ^ 9) a ?? eo-9,10-didehydro-2-thiomethyl-6-met i-8beta-methyl-13-cyano-ergoline.

Operating as in Example 24, but using 5beta (10-? 9) abeo-9, 10-didehydro-2-ti omet i 1-6-met i 1-8beta-met i 1-13-bromo-ergoli na instead of 5beta (10 - 9) -bee-9,10-didehydro-6-methyl-8beta-methyl-2-bromo-ergoline and potassium cyanide instead of sodium methoxide and cuprous cyanide instead of sodium methoxide and cuprous cyanide instead of cuprous iodide, the compound of the title was obtained in a yield of 45%, mp. 141-143 ° C.

Example 28 5beta (10- ^ 9) abeo-9, 10-dideshydro-6-raeti l-8beta-met i 1-12-aminocarboni 1-ergol ina.

Operating as in Example 15, but employing 5 betaOO- bebe-g, 10-di-dehydro-6-met i-8beta-methi-12-cyano-ergol i na instead of 5beta (10- "). ) abeo ~ 9, 10-didehydro-2 ^ cyano-6-methyl-8-beta-methyl-1-ergoline, the title compound was obtained in 65% yield, mp. 151-155 ° C.

Example 29 Beta- (10- ^ 9) abeo-9, 10-d ideshidro '-2-thiometi 1-6-met i 1-8beta-meti 1-13-ami nocarbonyl-ergoline.

A solution of 1.5 g of 5 beta (10-** 9) abeo-9, 10-didehydro-2-thiomethyl-1-6-methyl-8-beta-meth i-13-cyano-ergoline was heated to reflux. 1.5 g of potassium hydroxide ground in 30 ml of tert-butanol for 2 hours. The precipitate was filtered off completely, washed with water and recrystallized from acetone to give 0.7 g of the title compound, m.p. 155-158 ° C.

Example 30 5Beta- (10- »9) abeo-9, 10-didehydro-6-methyl-8beta-meth i-13-aminocarboni 1-ergoline.

Operating as in Example 23, but using 5beta (10- ^ 9) abeo-9, 10-didehydro-2-ti omet i 1-6 -met i-1 -bebe-met i 1-13-ami nocarboni 1-ergol ina instead of 5beta- (10 - * • 9) abeo-9, 10-d ideshidro -2-met i 11 i o-6-met i l-8beta-met i 1-12-bromo-ergol i na, the title compound was obtained in a yield of 30%, mp 138-141 ° C.

Example 31 Be ta (10 - ^> 9) abeo-9, 1 Q-didehydro-6-methy1 -8a 1 f a-met i 1-ergoli na.

Operating as in Example 3, but using 5beta (10 -? 9) abeo-9, 10-d ideshidro -6-met i-8alf a- (f in i lsul -f oni 1) met i 1-ergo 1 i na, instead of 5beta (10-09) abeo-9, 10-d ideshidro -6-met il-8beta- (phenylsulfonyl) methyl ergoline, the title compound was obtained in a yield of 40%, mp 185-190 ° C.

Example 32 5Beta (10 - »9) abeo-9, 10-d ideshidro -1, 6-d i me ti 1 -8 be t a-rae t i 1-ergol ina They were added to a solution of 3 g of 5beta- (10-9) abeo-9, 10-dideshydro < -6-met i-8beta-met i 1-ergoline in 30 ml.- of dimethyl sulfoxide, 0.6 g of freshly ground potassium hydroxide. After stirring for 15 minutes, 1.2 g of methyl iodide was added and stirring was continued for 20 minutes. The green solution was diluted with water and partitioned with ethyl acetate. After washing with brine and drying, the solvent was removed and the residue was filtered on a small pad of silica gel eluting with ethyl acetate. After 1-stablishment with diethyl ether, 1.9 g of the title compound, m.p. 126- 128 ° C.

Example 33 5Beta (10 - * 9) abeo-2, 3beta-di hi-dro-9, 10-ideshidro-6-met i 1-8beta-met i 1 -ergol i na and 5beta (10-99) abeo-2, 3 -di hi dro-9, 10-d ideshidro -6-meti l-8beta-meti 1-ergoline.

Portions were added portion by portion to a stirred solution of 5 g of 5beta (10? 9) abeo-9, 10-didehydro-6-raet i 1 -8beta-met i 1-ergol i na in 50 ml of trifluoroacetic acid , 1.7 g of sodium borohydride, under nitrogen. After 10 minutes of stirring, the resulting reaction mixture was diluted with water, basified with ammonium hydroxide and extracted with ethyl acetate. After drying, the solvent was removed and the residue carefully chromatographed on silica gel eluting with ethyl acetate. The fractions containing the less polar compound were accumulated and the solvent was removed. Crystallization with diethyl ether gave 3.1 g of 5beta (10 9) abeo-2, 3beta-di hi dr-9, 10-didehydro-6-met il-8beta-methyl-1-ergoli na, m.p. 179-182 ° C. Continuing the elution with the eluent of ethyl acetate / acetone, 95/5, the more polar compound was collected, after crystallization with diisopropyl ether, 0.35 g of 5beta (10 9) abeo-2, 3alpha- dihydro-9,10-d ideshydro-6-met i l-8beta-rae ti 1-ergoline, mp 143-148 ° C. 34 5Beta (10-? 9) abeo-2, 3beta-di hi-dro-9, 10-didehydro-i -aceti 1 -6-methyl-8beta-methyl-1-ergoline It was added to a solution of 2 g of 5beta- (10-> 9) abeo-2,3-dihydro-9, 10-didehydro-6-methyl-8beta-met i 1-ergoli in 50 ml of acetate of ethyl and 5 ml of trieti larai na, lg of acetic anhydride. After holding for 2 hours, the solution was washed with ammonium hydroxide, dried and evaporated. The residue was crystallized with isopropyl alcohol to give 1.8 g of the title compound, m.p. 142-144 ° C.

Example 35 5Beta (10- »9) abeo-2, 3a-l-a-dihi-dro-9, 10-d-ideshydro-1 -aceti-1 -6-met-1 -8-beta-methyl-1-ergoline.

Operating as in Example 34, but employing 5beta (10 -> 9) abeo-2, 3a 1 f a-dihi dro-9, 10-didehydro-6-methyl-8beta-met i 1-ergoli na, instead of 5beta (10 - »9) abeo-2,3beta-dihydro-9, 10-d ideshidro -6-methyl-8-beta-1-ergo-lina, the title compound was obtained in a yield of 70%, mp. 174-176 ° C.

Example 36 5Beta (10 -> 9) abeo-2,3beta-dihydro-9, 10-dihydro-1-araino-i - - - - - carboni 1-6-raet i 1-ergol i na.

Portions were added portionwise to a solution of 2 g of 5beta (10 -> 9) abeo-2, 3beta-di-hydro-9, 10-didehydro-6-methyl-8-beta-methyl-1-ergoline in 20 g. 0.1 N hydrochloric acid, 0.4 g of potassium cyanate at 0 ° C.

After stirring for 1 hour, the solution was basified with ammonium hydroxide and extracted with methylene chloride. After drying, the solvent was removed and the residue was crystallized with acetone to provide 1.3 g of the title compound, m.p. 220-222 ° C.

Example 37 5Alfa (10- ^ 9) abeo-9, 10-d ideshydro-6-rae ti l-8beta-met i 1-ergoline.

Operating as in Example 3, but employing 5a1 fa (10- * 9) abeo-9, 10-didehydro-6-methyl-8beta- (phenylsulfonyl) met i 1-ergoli na instead of 5beta (10). - "9) abeo-, 10-d ideshidro. -6-methyl-8beta- (phenylsulfonyl) methyl-ergo-lina, the title compound was obtained in a yield of 20%, mp 146-148 ° C.

Example 38 5Beta (10- ^ 9) abeo-6-methyl-8beta-methyl-10alpha-ergoline and 5Beta (10- »9) -6-met i-8beta-raet i-10beta-ergoline.

A solution of 5 g of 5beta- (10-* 9) abeo-9, 10-d ideshidro -6-met i-8beta-meti-ergoline 2 in 70 ml of ethanol and 2 g of Pd / C was hydrogenated. to 10%, 1.41 kg / cm (20 psi) of hydrogen at room temperature. The catalyst was completely filtered and the solvent was removed. The residue is carefully chromatographed on silica gel eluting with 1/1 cyclohexane / acetone to give 0.6 g of 5-beta (10-* 9) abeo-6-methyl-1-beta-methyl-1-alpha-ergoline, m.p. 265-268. Continuing elution with cyclohexane / acetone 2/3, 1.2 g of 5beta (I 0 -9) abeo-6-met i-8beta-methyl-lObeta-ergoline, m.p. 208-212 ° C.

Example 39 5Beta (10- "9) abeo-2, 3beta-dihi dro-9, 10-didehydro-6-methyl-1-beta-methyl-1,2-bromo-ergol i na, They were added dropwise to a stirred solution of 2 g of 5beta (10 - "9) abeo-l-acet i 1-2, 3beta-dihydro-9, 10-didehydro-6-met i-8beta-met il-ergoline in 30 ml of acetic acid and 1.2 g of bromine. After stirring for 1 hour, the resulting solution was diluted with ethyl acetate and partitioned with a 0.1M solution of sodium hydroxide. After drying, the solvent was removed in vacuo and the resulting reaction product was dissolved in 100 ml of 0.1 M hydrochloric acid and heated to reflux for 2 hours.

The resulting solution was basified with a concentrated solution of ammonium hydroxide and extracted further with ethyl acetate. After drying and removal of the solvent, the crude product was crystallized with acetone to give 1.3 g of the title compound, m.p. 175-178 ° C.

Example 40 5Beta (10 - = 9) abeo-2, 3beta-di-hydro-9, 10-didehydro-6-methyl-1-beta-methyl-12-nitro-ergoline.

They were added dropwise to a stirred solution of 5 g of 5beta (10-* 9) abeo-2, 3-beta-dihydro-, 10-didehydro-1-acetyl-6-methyl-8-beta-methyl. 1-ergoline in 50 ml of concentrated sulfuric acid, 3 ral of concentrated nitric acid at room temperature. After stirring for half an hour, the yellow reaction mixture was poured into crushed ice and basified with concentrated ammonium hydroxide solution. Extraction with ethyl acetate, drying and removal of the solvent gave a crude reaction mixture which was carefully chromatographed on silica gel, eluting with ethyl acetate / cyclohexane 5/3. The fractions were accumulated to give 3.8 g of a mixture of 5beta (10 - ^ 9) abeo-2, 3beta-9, 10-didehydro-1 -aceti 1-6-meti l-8beta-meti 1-12-ni tro -ergoline accompanied by the isomer 5beta (10 ->) abeo-2, 3beta-9, 10-didehydro-1-ace-t i 1-6-met i-8beta-meti 1-14-ni t- ergol ina. The mixture was dissolved in 100 ml of 0.1 M hydrochloric acid sol and heated to reflux for half an hour. After basification and extraction with ethyl acetate, the reaction mixture was crystallized with boiling ethanol to give 1.7 g of the title compound, m.p. 180-193 ° C. 41 5beta (10- »9) abeo-2, 3beta-di hi-dro-9, 10-didehydro-6-raeti-1 -beta-met i-1-nor tro-ergoline.

The mother liquor of the crystallization of 5beta (10- »9) abeo-2, 3beta-dihydro-9, 10-didehydro-6-methyl-8beta-methyl-12-nitro-ergoline in gel was placed in a column. silica eluting with acetone / cyclohexane 2/1. After evaporation of the solvent, the residue was critalized twice with acetone, leading to 0.6 g of the title compound, m.p. 156-159 ° C.

Example 42 5beta (10-9) abeo-9, 10-didehydro-6-met i-8beta-met i 1- 14-nitro-ergoline.

They were added to a solution of 1.5 g of 5beta- (10 - "9) -2, 3beta-dihydro-9, 10-didehydro-6-methyl-8beta-met i 1-12-ni t-ergol i na in 75 ml of dichloromethane, 5 g of freshly prepared manganese dioxide, after stirring for 8 hours, the suspension was filtered over celite, the solvent was removed and the residue was dissolved in acetone and applied to charcoal. concentration, 0.84 g of the title compound was obtained, mp 197-203 ° C.

Claims (12)

1. A compound of the formula I characterized in that: R, is a hydrogen, chlorine or bromine atom or a methyl, methylthio, hydroxy, cyano, nitro or carboxamido group; R.-, is an alkyl group of 1 to 3 carbon atoms or an allyl group; Ro and R are independently a hydrogen atom, an alkyl group of 1 to 5 straight or branched carbon atoms, a straight or branched alkenyl group of 3 to 5 carbon atoms, a cycloalkyl group of 5 to 6 carbon atoms alkyl of 1 to 3 carbon atoms, a phenylalkyl group of 1 to 3 carbon atoms, a phenyl 1 alkenyl group of "3 to 5 carbon atoms or phenyl: groups that are optionally substituted by alkyl of 1 to 3 carbon atoms , alkoxy of 1 to 3 carbon atoms, rifluoromethyl, hydroxy or amino group; I6 group of the formula -C-R7 wherein R is a hydrogen OH atom or an alkyl group of 1 to 3 carbon atoms and R7 is a phenyl group or substituted phenol group as described above or a heterocyclic ring having 5 or 6 members in the ring, including 1 or 2 hetero atoms independently selected from oxygen, sulfur and nitrogen; the dashed lines in positions 2-3 and 9-10 independently represent a single link or a double link; Rr is a hydrogen, bromine, fluorine or iodine atom or a methoxy, cyano, carboxamido, nitro, methylthio or trifluoromethyl group or a group of the formula NRQRQ wherein Ro and RQ are independently a hydrogen atom, or an alkyl group from 1 to 3 carbon atoms, acetyl, methanesul foni 1 ootrif luoroacet i lo; and R represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms straight or branched, meta-sulfonyl or acetyl or a group of the formula CONRQRQ wherein Rg and Rg are as defined above; a pharmaceutically acceptable salt thereof
2. 2. A compound according to claim 1, of the formula I ' characterized in that R, R,, R ~, Ro, R, and Rr are as defined in claim 1 and the wavy lines (^ Vw '») mean that the hydrogen atoms and the CHR-R group may be in the alpha or beta position with respect to the plane of the rings; or a pharmaceutically acceptable salt thereof.
3. 3. A compound of formula I 'according to claim 2, characterized in that R represents a hydrogen atom, or a cyano or carboxamido group, R 2 represents a methyl group, R o represents a hydrogen atom, R represents a group of the formula -CH (0H) Fen, R5 represents a hydrogen, fluorine or iodine atom, or a methoxy, methylthio, trifluoromethyl, nitro or carboxamido group or a group of the formula NRQRQ, wherein Rfi and RQ are independently a Hydrogen atom or an alkyl group of 1 to 3 carbon atoms, acetyl, methanesulfonyl otrif 1 by oacet i lo and the hydrogen atom in position 5 and the residue in position 8 are both in the beta position.
4. 4. A process for the preparation of a compound of the formula I and its acid addition salts, according to claim 1, the process is characterized in that it comprises: a) reacting a compound of the formula II wherein R2, Ro and R, are as defined in claim 1, with a reducing agent, and b) optionally converting the resulting compound of formula I, into another compound of formula I, wherein one or more of R, R ^, Rr have been altered by one or more appropriate chemical reactions.
5. 5. A process for preparing a compound of the formula II according to claim 4, characterized in that it is prepared by the reaction of an alkaline salt of a compound of the formula III wherein R ~ is as defined in claim 4, either with a compound of the formula RoY, wherein Ro has the meaning given in claim 4, and Y is a leaving group; or with a compound of the formula R, C0R., wherein R, and R_ have the meanings given in claim 1 and, if desired, reacting an alkaline salt of the resulting compound with either a compound of the formula R , Y, wherein Y is as defined above and R, is as defined in claim 4, or with a compound of the formula R5COR7, wherein R & and R-, have the meanings given previously.
6. 6. A process for preparing a compound of the formula III according to claim 5, characterized in that it comprises reacting a compound of the formula IV wherein Rj is as defined in claim 5 with an oxidizing agent.
7. 7. A process for preparing a compound of formula IV according to claim 6, characterized in that it comprises reacting a compound of formula V wherein R is as defined in claim 6 with (FenS) or »and (n But)" P in a solvent or by reacting a compound of the formula (VI) wherein R ,, is as defined above and Y is as defined in claim 5, with FenSNa in a solvent at a temperature ranging from 80 ° C to 120 ° C.
8. 8. A process for preparing a compound of formula III according to claim 5, characterized in that it comprises reacting a compound of formula VI as defined in claim 7 with FenS0 ~ Na in a solvent at a temperature ranging from 80 °. C at 140 ° C.
9. 9. A pharmaceutical composition, characterized in that it comprises a compound of the formula I according to claim 1, 2 or 3 or a pharmaceutically acceptable salt thereof in admixture with an acceptable diluent or carrier.
10. 10. A compound of the formula I according to claim 1 or a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body by therapy.
11. 11. A compound or salt according to claim 10, characterized in that it is for use in the treatment of central nervous system disease.
12. 12. Use of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of central nervous system disease. In testimony of which I sign the present in this City of Mexico, D. .. on December 13, 1995. ADoderado SUMMARY OF THE INVENTION Compounds of the formula (I) are provided, wherein R. is a hydrogen, chlorine or bromine atom or a methyl, methylthio, hydroxy, cyano or carboxamido group; R ~ is an alkyl group of 1 to 3 carbon atoms or an allyl group; R "and R are independently a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, an alkenyl group of 3 to 5 carbon atoms, a cycloalkyl group of 5 to 6 carbon atoms-alkyl of 1 to 3 carbon atoms, a phenylalkyl group of 1 to 3 carbon atoms, a phenylalkyl group of 3 to 5 carbon atoms or a phenyl group: groups which are optionally substituted by alkyl of 1 to 3 carbon atoms, alkoxy from 1 to 3 carbon atoms, trifluoromethyl, hydroxy or amino; or a group of the formula (a), wherein R, is a hydrogen atom or an alkyl group of 1 to 3 carbon atoms and R7 is a phenyl group, a substituted phenyl group as described above or a heterocyclic ring, You laugh a hydrogen or bromine atom or an organic residue and R is H or an organic residue or a pharmaceutically acceptable salt thereof. A process for their preparation and the pharmaceutical compositions containing them are also provided.