CS245790B2 - Production method of ergoline derivatives - Google Patents

Description

The invention provides a process for the preparation of ergoline derivatives of the general formula I

in which

R1 represents a hydrogen atom or a methyl group,

R2 represents a hydrogen atom, a halogen atom, a methyl group, a cyano group, a C1-C4 alkylthio group or a phenylthio group,

R 7 and R 6 are hydrogen and R 3 is hydrogen or methoxy, or

R 7 represents a hydrogen atom and R 3 and R 6 together form a bond, or

R 3 represents a hydrogen atom or a methoxy group and R 2 and R 5 together form a bond,

R a is a C 1 -C 4 hydrocarbon radical,

R 5 represents a hydrogen atom or a phenyl group,

X represents an oxygen atom, a sulfur atom or an imino group,

W represents an oxygen atom or an imino group,

A represents a radical of formula CHRe, CH 2 - CHRe or CH = CR 6, wherein R 6 represents a hydrogen atom or a C 1 -C 4 alkyl group and n is a number of 0, 1 or 2.

The invention also encompasses the preparation of pharmaceutically acceptable salts of these ergoline derivatives.

The term " halogen " for R2 preferably includes chlorine and bromine, but is also fluorine. The C1 -C4 hydrocarbon radicals R @ 1 and R @ 5 are the corresponding alkyl groups, cycloalkyl groups and unsaturated groups, which may contain both a double and a triple bond. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, butyl, tert -butyl, isobutyl. cyclopropyl, methylcyclopropyl, vinyl, allyl and propargyl.

By pharmaceutically acceptable salts is meant those salts which retain the biological activity and properties of the free bases and which are not biologically or otherwise undesirable. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, and with organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, acid malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

R1, R2, R3, R7, R6 and R5 are preferably hydrogen. Preferably R4 is methyl and n is 1.

Preferably W and X are oxygen atoms and A is -CH 2 - or CH 2 -CH 2 -, most preferably -CH 2 -.

The present invention provides a process for the preparation of the compounds of the formula I as described above, characterized in that the ergoline derivative of the formula II is used

in which

R 1, R 2, R 3, R 1, R 7, R 5, A and n are as defined above, and

B is cyano, C 2 -C 5 alkoxycarbonyl or carbamoyl condensed with a compound of formula III

X = C = N = R 5 (III) wherein

R 5 and X are as defined above.

The resulting intermediates are then cyclized to the compounds of formula I as defined above.

. The condensation reaction may be carried out in a solvent such as water, ethanol, acetic acid or pyridine, optionally with the addition of an acid such as hydrogen chloride, at a temperature of from 50 to 100 ° C.

The cyclization may be carried out in the same environment as the condensation, or may be accomplished by heating the isolated intermediate in a vacuum of 13 to 200 Pa to a temperature of 130 to 160 ° C. After completion of the reaction, the crude product can be purified by crystallization or chromatography.

The ergoline derivatives of the general formula (II) used as starting materials in the process according to the invention are either known or can be prepared from known compounds by conventional methods. According to one preferred method, compounds of formula II wherein A is CH2-CHR3 can be obtained by reacting the corresponding ergoline primary amino derivative with an acrylate derivative of the formula

Re

AND

CH 2 = C-B wherein

R 6 and B are as defined above.

Alternatively, a compound of formula (I) may be used

Re

AND

Br (CH 2) _{m -} CH - B wherein

R6 and B are as defined above, and m is 0 or 1, reacted with the corresponding primary amino derivative ergoline to form compounds of formula II.

The compounds of formula III which are used as further starting materials in the process according to the invention are known and can be prepared in situ by reacting the corresponding salt thereof with an acid, such as hydrochloric acid.

The free base forms of the compounds of formula (I) may be converted in conventional manner into acid addition salts and vice versa.

The compounds produced by the process of the invention and their pharmaceutically acceptable salts show pharmacological activity.

For example, these compounds inhibit prolactin secretion, as evidenced by the Inhibition of Fertilized Egg Implantation in the Uterus of Rat Females on the fifth day after insemination (see E. Fluckiger et al., Hand. Exp. Pharmac., 49, 615, 1978).

The compounds of the invention and their salts are particularly effective as antihypertensive agents.

Anitihypertensive efficacy tests:

Indirect systolic blood pressure measurements are performed on groups of four spontaneously hypertensive rats (SHR, Kyo245790's, Charles River, Italy) aged 8 to 10 weeks.

In order to stabilize the pulse pressure, the animals are kept for 10-15 minutes in an environment of 36 ^° C, and systolic blood pressure and heart rate (W + W, BP Recorder, model 8 005) are measured indirectly using the cuff on the tail of the test animal. Test substances are administered orally in suspension in 5% gum arabic, once daily for 4 consecutive days, measured prior to treatment and then on the first and fourth days of the test at 1 and 5 hours after dosing. The doses of the test substances correspond to those of the free bases. Control animals receive only vehicle (0.2 ml / 100 g body weight).

Hydralazine (1-5 mg / kg, orally) and α-methyldopa (30-100 mg / kg orally) were also tested as standard comparators. Changes in systolic blood pressure and heart rate induced by the test substance are calculated as deviations from pre-treatment values and are reported as an average of the values obtained in 4 animals.

Results of anlihyp-erteinsive efficacy tests

Tables 1 and 2 below show the results obtained with the compounds of the invention, together with those obtained in vehicle-treated control animals and those obtained in animals treated with two standard comparatives, i.e. hydralazine and α-methyldopa. In vehicle-only treated rats, systolic blood pressure (SKT) and heart rate (SF) remain stable throughout the experiment, while all test substances reduce SKT very effectively at oral doses ranging from 1 to 20 mg / kg. This effect is not accompanied by a reflective increase in SF, but a slight decrease in SF was observed.

The air-acting activity of all compounds is rapid and remains very pronounced throughout the experiment. These effects are similar on both the first and fourth day of the test, indicating that the compounds of the invention do not have tachyphylaxis. In particular, the compounds prepared in Examples 1 and 2 show very pronounced and long-lasting efficacy without a significant change in heart rate.

Compared to standard comparators, the compounds of Examples 3, 5, 7, 9, 12, 16, 17 and 21 (tested at doses ranging from 1 to 7.5 mg / kg orally) are more potent than hydralazine (1). up to 5 milligrams / kilogram per os) and N-methyldopa (30 to 100 mg / kg per os) without inducing the reflexive increase in heart rate observed with the latter standard substances.

Table 1

Effect on systolic blood pressure (SKT) of rats (SHR); mean deviations from the condition in untreated control animals (groups of 4 rats) compound dose change in SKT (Δ Pa) (mg / kg per os) Day 1 Day 4

1 2 1 hour after administration 3 5 hours after administration 4 1 hour after administration 5 5 hours after administration 6 carrier-environment - + 333.3 - 999.8 - 853,2 - 666.5 from Example 1 20 May - 11997,0 - 8 331.3 - 8 331.3 - 6 158.5 from Example 2 20 May - 7,998.0 - 9 664.3 —11,997.0 - 8 331.5 from Example 3 7.5 - 7 331.5 - 7,491.5 - 7 331.5 - 7 158.3 from Example 5 7.5 - 6 825.0 - 8 664.5 —10,997.5 - 7 331.5 from Example 7 7.5 - 4 998.8 - 3,492.5 - 6 665.0 - 4,225.7 from Example 9 1 - 2 666.0 - 3,817.1 - 5 825.3 - 6 998.3 from Example 12 15 Dec - 6 665.0 - 4,492.3 - 8 331.3 - 3 159.3 from Example 16 20 May - 6 825.0 - 7,998.0 —11 330.5 - 9 664.3 from Example 17 5 - 5 158.8 - 8 891.2 - 5,558.7 - 5 105.4 from Example 21 1 - 3 665.8 - 4159,0 - 9 331.0 - 3 999.0 hydralazine 1 5 - 679,9 - 5 358.7 - 2 092.9 - 2 666.0 - 665.5 - 2 719.4 - 40.0 - 933.1 «-Methyldoipa 30 100 ALIGN! - 1386.4 - 1333.0 - 2 679.4 - 3,385.9 - 1333,0 - 2 692.7 + 66.7 - 3,332.5

24S790

Table 2

Effect on heart rate of treated control animals (SF) in rats (SHR); mean deviations from the status at no (groups of 4 rats) changes in SF (beats / min) compound 1 dose (mg / kg per os) 2 1 day Day 4 1 hour after administration 3 5 hours after administration 4 1 hour after administration 5 5 hours after administration 6 carrier environment - - 5,0 + 12.0 —10.0 —19.0 20 May + 4.0 —40.0 —33.0 - 8,0 from Example 1 20 May —20 —10.0 —25.0 - 7.0 from Example 2 7.5 —37.0 —20.0 —42.0 —10.0 from Example 3 7.5 —60.0 —32.0 —75.0 —28.0 from Example 5 7.5 + 13.0 —35.0 + 37.0 —20.0 from Example 7 1 —28.0 - 8,0 —60.0 —35.0 from Example 9 15 Dec —18.0 —32.0 —35.0 + 15.0 from Example 12 20 May - 8,0 + 17 + 42.0 —18.0 from Example 16 5 —23.0 +17.0 + 30.0 —27.0 from Example 17 1 —13.0 —23.0 + 15.0 —15.0 from Example 21 1 + 30.0 + 35.0 + 25.0 + 15.0 hydralazine 5 + 40.0 + 45.0 + 18.0 + 15.0 α-methyldopa 30 + 35.0 + 40.0 + 45.0 + 30.0 100 ALIGN! + 70.0 + 40.0 + 50.0 + 10,0 The invention further provides pharmaceutical Example 1

compositions comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier. The compounds of formula I and their non-toxic pharmaceutically acceptable acid addition salts or mixtures thereof can be administered either parenterally or orally, preferably 6-methyl-8/3 - [(1H, 3H) -2,4-dioxodihydro-1- pyrimidinylmethyl] ergoline

I: R1 - R2 = R3 - R7 Re ⁼ H,

R ₄ = CH}, n = l,

A = CH 2 CHR 6, Re = H,

W = X = O, R 5 = H.

No.

As used herein, the term "effective amount" refers to an amount that provides the desired degree of efficacy without causing undesirable side effects. The effective dose is generally in the range of about 0.001 to 0.5 mg / kg / day, preferably 0.1 to 0.25 mg / kg / day.

The pharmaceutical carriers that are usually used in combination with the compounds of the invention may be solid or liquid and generally selected depending on the intended route of administration. For example, solid carriers include lactose, sucrose, gelatin, agar, and the like; liquid carriers include water, syrup, peanut oil, olive oil, and the like.

The selected compound and carrier can be formulated into a variety of dosage forms, such as tablets, capsules, suppositories, solutions, emulsions, powders and syrups.

The invention is illustrated by the following non-limiting examples.

A mixture of 5.1 g of 8 (3-aminomethyl-6-methylergoline and 1.8 ml of methyl flikirylate ¹ in 100 ml of methanol) was refluxed for 4 hours, the solvent was evaporated under reduced pressure and the residue was crystallized from diethyl ether. 6 g of 6-methyl-8 / 3- [N- (2-methoxycarbonylethyl) aminomethyl] ergoline are obtained (II: R1 = R2 = R3 = R7 = R8 = H,

R4 = CH3, n = 1, A = CH2-CHRe,

R (j = H, B CCOOCH ·), m.p. 130-132 ° C.

To a solution of 2.86 g of potassium cyanate in 30 ml of water is added a solution of 6 g of 6-methyl-8 / 3- [N- (2-methoxycarbonylethyl jaminoethyl) ergoline in 120 ml of water and 35 ml of 1 N hydrochloric acid. The resulting solid was filtered and recrystallized from ethanol to give 4.5 g of the title compound, m.p.

330 ° C.

Example 2

6-Methyl-8β- (2,4-dioxo-1-imidazolidinylmethyl) ergoline

I: R: = R2 = R3 = H; R4 = CH3; n = 1; A = CHRe; Ro = H; R7 = R8 = R5 = H; W = X = O

To a warm solution of 6 g of 8 (S-aminomethyl-6-methylergoline in 90 ml of dimethylformamide) was added a solution of 1.3 ml of ethyl bromoacetate in 30 ml of dimethylformamide, and after completion of the reaction, the resulting solution was concentrated by evaporation in vacuo. extract with chloroform.

The organic layer was evaporated in vacuo and the residue was purified by silica gel column chromatography using a 9: 1 by volume mixture of ethyl acetate and methanol as eluent. 3.5 g of 6-methyl-8,5- (N-ethoxycarbonylmethylaminomethylaminomethyl) ergoline are obtained (II: R 1 = R 2 = R 3 = H, R 1 = CH 2, n = 1, A = CHR ₆ , R 5; B- = CO _{2 (} C ₂ H ₅ ), which melts at 174-176 ° C after recrystallization from diethyl ether.

3.5 g of 6-methyl-8 / 3- (N-ethoxycarbonylmethylaminomethyljergoline) was treated with 1.75 g of potassium cyanate as described in Example 1. The title compound melting above 300 ° C was obtained in 72% yield.

Example 3

6-Methyl-8β - [(1H, 3H) -2,4-dioxo-3-methyldihydro-1-pyrimidinylmethyl] ergoline

I: r _{1 =} r ₂ = r ₃ = h, r ₄ = CH 3, n = 1,

A CH2CHRs = R6 = H, R5 = CH3, _R7 = _R8 = H, X = W = 0

A mixture of 8.5 g of 6-methyl-8 (3- [N- (2-methoxycarbonylethyl jaminomethyl) ergoline) prepared as described in Example 1j with 2.95 ml of methyl isocyanate in 100 ml of pyridine is heated at 60 ^DEG C. for 1 hour. evaporation of the solvent gave, after crystallization from methanol, 8.5 g of 6-methyl-8β- [N- (2-methoxycarbonylethyl) -N-methylcarbamoylaminomethyl] ergoline melting at 140-142 ° C.

Heating of the above 6-methyl-8 - S - [N- (2-methoxycarbonylethyl) -N-methylcarbamoylaminomethyl] ergoline under vacuum at 145 ° C for one hour afforded 6.5 g of the title compound which melts after crystallization from methanol at Mp 118-120 ° C.

Example 4

6-Methyl-8 / 3- (2,4-dioxo-3-methyl-1-imidazolidinylmethyl) ergoline

I: R 1 = R 2 = R 3 = H, R 4 = CH 3, n = 1,

A = CHR a, R 3 = R 7 = R 8 = H, R 5 = CH 3,

W = X = Q

The procedure is analogous to that in Example 3 except that 6-methyl-8,3- (N-ethoxycarbonylmethylaminomethyl) ergoline (prepared according to the procedure described above) is used instead of 6-methyl-8β- [N- (2-methoxycarbonylethyl) aminomethyl] ergoline. according to Example 2). To give 6-metihyl-8'jS '- (No ⁱ tihiO'xyka! Rbonylmethyl N methylkarbamoylaminomethyl) ergoline, m.p. 165-167 ° C.

Heating of 6-methyl-8β- (N-ethoxycarbonylmethyl-N-methylcarbamoylaminomethyl) ergoline under vacuum at 140 degrees Celsius for 1 h afforded the title compound in 77% yield, melting at 250 ° C with decomposition.

Example 5

6-Methyl-8 S - [(1 H, 3 H) -2 1,4-dioxo-3-propyl-dihydro-1-pyrimidinylmethyl] ergoline

I: R 1 = R 5 == R 3 = H, R 4 = CH 3, n = 1, A = CH 2 CHR 6, R 5 = R 7 = R 8 = H, R 5 = CH 2 CH 2 CH 3, x = w = o

The procedure is analogous to Example 3 except that propyl isocyanate is used instead of methyl isocyanate.

The yield of the product melting at 201 DEG-202 DEG C. was 60%.

Example 6

6-Methyl-8S - [(1H, 3H) -2,4-dioxo-3-isopropyldihydro-1-pyrimidinylmethyl] ergoline

I: R 1 R 2 R 5 R h, R 1 -CH 2, n = 1,

A = CH 2 CHR 5, Re = R 7 = R 8 = H,

R 5 = CH (CH 3) 2, x = w = o

The procedure is analogous to Example 3 except that isopropylcyanate is used instead of methyl isocyanate. After heating at 150 ° C for 2 hours (instead of heating at 145 ° C for 1 hour), the title compound is obtained in a yield of 60%, m.p. 175-177 ° C.

Example 1 a d 7

6-Methyl-8S- (2,4-dioxo-3-propyl-1-imidazolidinylmethyl) ergoline

I: R = R ₂ = R 3 = H, R 4 - CH, n = l,

A = CHR5, R6 = R7 = R8 = H,

R 5 = CH 2 CH 4 CH 3, x = w = o

The procedure is analogous to that of Example 4 except that propyl isocyanate is used instead of methyl isocyanate. Yield: 55%. Mp 188-190 ° C.

Example8

6-Methyl-8 / 3- (2,4-dioxo-3-isopropyl-1-imidazolidinylmethyl) ergoline

I: R 1 = R 2 = R 5 = H, R 6 = CH 3, n = 1,

A = CHR 6, R 6 = R 7 = R 8 = H,

R 5 = CH (CH 3) 2, x = w = o

The procedure is analogous to that in Example 4 except that isopropyl isocyanate is used instead of methyl isocyanate. After heating in vacuo at 160 ^° C for 2 hours (instead of 140 ° C for 1 hour), the title compound is obtained in 75% yield, m.p. 210-212 ° C.

Example 9

6-Methyl-8H- {2 - [(1 H -1,3H) -2,4-dihydro-dihydro-1-pyrimidinyl] ethyl] uroline

I: R 1 = R 2 = R 3 = H, R 4 = CH 3, n = 2,

A = CH 2 CHR 6, R 5 = R 6 = R 7 = R 8 = H,

W = X-0

The procedure of Example 1 was carried out using 8β-aminoethyl-6-methylergoline instead of 8β-aminomethyl-6-methylergoline. Yield 74%, mp 140-142 ° C.

Example 10

6-Methyl-8 (S- [2- (2,4-dioxo-1-imidazolidinyl) ethyl] ergoline

I: R = R ₂ = R ₃ = H, R4-CH 3, n = 2,

A = CHRe, R 5 = R 6 = R 7 = R 8 = H,

X = W = 0

The procedure is analogous to that of Example 2 using 8β-aminoethyl-6-methylergoline instead of 8β-aminomethyl-6-methylergoline. Yield: 68%, mp 242-244 ° C.

Example 11

6-Methyl-8, 3 - [(1H, 3H) -2,4-dioxodihydro-1-pyrimidinyl] ergoline

I: Ri. = R2 = R5 = H, R4 = CH3, n = O,

A = CH 2 CHR 6, R 5 = R 6 = R 7 = R 8 = H, x = w = o

Using an analogous procedure as in Example 1, substituting 8? -Amino-6-methylergoline instead of 8? -Aminomethyl-6-methylgololine yields 79% of the title compound, melting at 312-314 ° C.

Example 12

6-Methyl-8 / 3- (2,4-dioxo-1-imidazolidinyl) ergoline

I: Ri = _R2 = R3 = H, R4 = CH3, n = 0,

A = CHR 6, R 5 = R 5 = R 7 = R 5 = H, x = w = o

Working in analogy to Example 2, substituting 8-amino-6-methylergoline instead of 8- (3-aminomethyl-6-methylergoline) yielded the title compound in 80% yield, mp 295-297 Deň: 32 ° C.

Example 13

1,6-Dimethyl-8 '- [(1H, 3H) -2,4-dioxodihydro-1-pyrimidinylmethyl] ergoline

I: R 2 = R 3 = R 5 = R 6 = R 7 = R 8 = H,

Ri = _R4 = CH3, n = l, A = CH 2 CHR

X = W = 0

Analogously to Example 1, using 8/3-aminomethyl-6-dimethylergoline instead -8/3-Aminomethyl-6-methyl-ergoline obtained in 75% yield the title compound, melting at 314-316 ^C NO. Example 14

1,6-Dimethyl-8β- (2,4-dioxo-1-imidazolidinylmethyl) ergoline

I: R2 = R3 = R5 = Re = R7 = Ra = H,

R 1 = R 4 = CH 3, n = 1, A = CHR e,

X = W = 0

Using the procedure analogous to Example 2, using 8β-aminomethyl-1,6-dimethylergoline instead of 8β-aminomethyl-6-methylergoline, the title compound is obtained in a yield of 65%, melting at 292-294 ° C.

Example 15

6-Methyl-10-methoxy-8 / 3- (2,4-dioxo-1-imidazolidinylmethyl) ergoline

I: R 1 = R 2 = R 5 = R 6 = R 7 = R 8 = H,

R 3 = OCH ₃ , R 1 -CH 3, n = 1, A = CHR e, x = w = o

Using the procedure analogous to Example 2, using 8β-aminomethyl-6-methyl-10-methoxyergoline instead of 8β-aminoniethyl-6-methylergoline, the title compound is obtained in a yield of 68%, melting at 234-236 ° C.

Example 1 a d 1 6 - ’

6-Methyl-8 (3 - [(1H, 3H) -2,4-dioxo-1-pyrimidinylmethyl] ergoline

I: R1 = R2 = R1-R5-R5-R7-Ro-H,

R1 = OCH2, n = 1, A = CH = CR6 ,. :

X = W —O

The same procedure as in Example 1 was followed except that 6-methyl-8 H - {(2-ethoxycarbonylvinyl) -] was substituted for 6-methyl-8 / 3- [N- (2-methoxycarbonylethyl-aminomethyl) ergoline]. 3-Aminomethyl] ergoline in 48% yield, the title compound melting above 320 ° C.

Example 17

6-Motliyl-8,4-f (1H) -2-thioxo-4-oxotetrahydro-1-pyrimidinylmethyl] ergoline - _; . ,,: I :: R 1 = R 2 = R 5 = R 5 -R 6 = R 7 -Rfr == Hi R 1 = CH.;

The procedure is analogous to Example 1 except that potassium thiocyanate is used instead of potassium cyanate. The title compound, m.p. > 300 ° C, is obtained in 58% yield.

Example 18

6-Methyl-8/3 - [(1H) -2-thioxo-4-oxo-3-methyltetrahydr o-1-pyrimidinylmethyl] ergoline: R1 = R'1-R3-R5-R7 = R8- H, R 4 = R 5 = ch 3, n = i, A = CH 2 CHR 6, w = o, x = s

The procedure is analogous to Example 1 except that methyl isocyanate is used instead of potassium cyanate. Yield 74 ° / o, the title compound, melting at 266-268 ° C.

Example 19 ·. ···. · -. ··

6-n-Propyl-8S - [(1H) -2-thioxo-4-oxo-3-methyltotrahydro-1-pyrimidinyl-methyl] ergoline

I: R1 = R2 = R3 = R6 = R7 = R8 = H;

R 1 - n - C 3 H 7, R 5 = CH 3, n == 1, A-CH 2 CHR 6, x = s, w = o

The procedure is analogous to that in Example 18 except that 8β-aminomethyl-6-n-propylergoline is used instead of 8β-aminomethyl-6-methylergoline. The title compound is obtained. Yield 63%.

Example 1 a d 2 0

6-Ally 1-8 $ [(1 H) -2-thioxo-4-oxo-3-methyltetrahydro-1-pyrimidinylmethyl] ergoline

I: Ri = R2 = R3 = R6 - R7 = R8 = H, R4 allyl, R ₃ = CH _b n-1, A = CH, CHR _6, W = O, X = S

The procedure is analogous to that of Example 18 except that 8β-aminomethyl-6-allylergoline is used instead of 8β-aminomethyl-6-methylergoline. Yield: 77%.

Example 21

Methyl-8 / 3- (2-thioxo-4-oxo-3-methyl-1-imidazolldinylmethyl) ergoline

I: R 1 = R 6 = R 3 - R 5 —R 7 —R 8 —H,

R4 = R5 = CH3, n = 1, A = CHRe,

W = 0, X = S

The procedure is analogous to Example 2 except that methyl isothiocyanate is used instead of potassium cyanate. The title compound is obtained in 83% yield, mp 263-265 ° C. .

Example 22

Propyl-8/3: (2-thioxo-4-oxo-3-methyl-1-imidazolidinylmethyl) ergoline

I: R 1 = R 2 = R 5 = R 6 = R 7 = R 8 = H,

R4 = n-C3H7, R5 = CH3, n = 1, A = CHR6,

W = 0, X = S

In analogy to Example 21, using 8β-aminomethyl-6-propylergoline instead of 8 ₍ 6-aminomethyl-6-methylergoline), the title compound is obtained in 88% yield.

Example 23

6-Ally 1- [3- (2-thioxo-4-oxo-3-methyl-1-imidazolidinylmethyl) ergoline]

I: R1 = R2 — R3 = R6 = R7 = R8 = H,

R 1 = allyl, R 5 -CH 3, n = 1, A = CHR e,

W = 0; X = S

Using the procedure analogous to Example 2, using 8β-aminomethyl-6-allylergoline instead of 8β-aminomethyl-6-methylergoline, the title compound is obtained in a yield of 69%.

Example 24

6-Methyl-S / 3 - [[1H, 3H) -2-oxo-4-iminodihydro-1-pyrimidinylmethyl] ergoline

I: R1 - R2 ⁼ R5 ⁼ Rf1 = 7 ⁼ R1 - H, R3 = OCH3, n = 1, A = CHRe, X = W = 0

I: R1 = R2 = R3 = R5 = R6 = R7 = R5 = H,

R4 = CH3, n = 1, A = CH2CHR6,

W = NH, X = O

24S790

A mixture of 6-methyl-8 ₍ 6- [N- (2-cyanoethyl) aminomethyl isirgolinium [prepared according to Example 1 but using acrylonitrile instead of methyl acrylate), aqueous potassium cyanate, and 1N hydrochloric acid was heated at 60 ° C for 1 hour. The solution was neutralized with 1 N sodium hydroxide and extracted with chloroform, the organic layer was evaporated and the residue was purified by silica gel chromatography to give 80% yield of (methyl-.alpha .- (N-(2-cyanethyl) N-carbamoylaminomethyl jergoline). mp 252-254 ° C.

This product was heated in vacuo at 150 ° C for 1 hour in 45% yield to give the title compound, mp 248-250 ° C.

Example 25

2-Bromo-6-methyl-8 / 3- (2,4-dioxo-1-imidazolidinylmethyl jergoline)

I: R 1 = R 3 = R 5 = R 5 = R 7 = R 5 = H, R 2 = Br,

R 4 = CH 3, n = 1, A = CHR 6, X = W = O

The procedure is analogous to Example 2 except that 8β-aminomethyl-2-bromo-6-methylergoline is used instead of 8β-aminomethyl-6-methylergoline.

The title compound, m.p. 279-281 ° C, is obtained in 64% yield.

Example 26

2,6-Dimethyl-8 ₍ S- (2,4-dioxo-1-imidazolidinylmethyl jergoline)

I: R 1 = R 3 = R 5 = R 6 = R 7 = Re = H, r ₂ = R 4 = CH 3, n = 1, A = CHR 6, X = W = 0

The procedure is analogous to that of Example 2 except that 8R-aminomethyl-2,6-dimethylergoline is used in place of 8, d-aminoethyl-6-methylergoline. Yield: 75%. Mp 215-217 ° C.

Example 27

2-Thiomethyl-6-methyl-8 / 3- (2,4-dioxo-1-imidazolidinylmethyl) jergoline

I: R1 = R3 = R5 = R6 = R7 = R8 = H, R2 = SCH3,

R 4 = CH 3, n = 1, A = CHR ₆ , X = W = 0

Using the procedure analogous to Example 2, the title compound, m.p. 255 DEG-257 DEG C., was obtained in 8% yield with 62% yield of 62%.

Example 28

6-n-Propyl-8 / 3- (2,4-dioxo-1-imidazolidinylmethyl jergoline)

I: Ri = R2 = R3 = R5 = H 7-RJ3 ^í = R8 = H;

R ₄ = n-C3H7, n = l, A = CHR, X = W = O

The procedure is analogous to Example 2 except that 8β-aminomethyl-6-n-propylergoline is used instead of 8β-aminomethyl-6-methylergoline. The title compound is obtained in 80% yield, m.p. 168-170 ° C.

Example 29

6-Methyl-8α- (2,4-dioxo-1-imidazolidinylmethyl jergoline)

I: R1 = R2 * ^and R3 ^XE R5 = sR5 = R7 = Re — H,

R ₄ = CH 3, n = l, A = CHR, X = 0 == W

The procedure is analogous to that of Example 2 except that 8α-aminomethyl-6-methylergoline is used instead of 8-aminomethyl-6-methylergone. The title compound of m.p. 199 DEG-201 DEG C. is obtained in 58% yield.

Example 30

6-Methyl-8- [(1H, 3H) -2,4-dioxo-dihydro-1-pyrimidinylmethyl] -8,9-didehydroergoline

I: R1 = R2 = R3 = R5 = R6 ^3s H, R4 = CH3,

R 7 and R 8 form a bond, n = 1, A = CH 2 CHR 6, X = W == 0

Analogous to Example 1, using 8-aminomethyl-6-methyl-8,9-didehydroergoline in place of 8'-aminomethyl-6-methylergoline in 63% yield, the title compound melting at 190-192 ° C.

Example 1 a d 3 1

6-Methyl-8- (2,4-dioxo-1-imidosolidinylmethyl) -8,9-didehydroergoline

I: R 1 = R 2 == R 3 = R 5 = R 6 = H, R 1 = CH 3,

R 7 and R 8 form a bond, n = 1, A = CHR 0, X = W = O

The procedure is analogous to that of Example 2 except that N, N-aminomethyl-ε-methyl-ε-didehydroergoline is used instead. Yield 72%, mp 204-206 ° C.

Example 32

6-Methyl-8β - [(1H, 3H) -2,4-dioxohydro-1-pyrimidinylmethyl] -9,10-didehydroergoline

I: R = _R2 = R5 = R6 = R7 = H,

R3 and Re form a bond,

R 4 = CH 3, n = 1, A = CH 2 CHR 6, X = W = 0

In analogy to Example 1, using 8β-aminomethyl-6-methyl-9,10-didehydroergoline instead of 8β-aminomethyl-6-methylergoline, the title compound is obtained in a yield of 77%, melting at 290-292 ° C. C.

Example 33

6-Methyl 1-8 / 3- (2,4-dioxo-1-imidazolidinylmethyl) -9,10-didehydroergoline

I: R 1 = R 2 = R 5 = R 6 = R 7 = H,

Ro and Ra form a bond,

R 1 = CH 3, n = 1, A = CHR e, X = W = 0

Analogous to Example 2, substituting 8,6-aminomethyl-6-methyl-9,10didehydroergoline in place of N, N-aminomethyl-6-methylergoline yields 78% of the title compound, m.p. 282-284 ° C. .

Claims (1)

A process for the preparation of ergoline derivatives of the general formula I in which: R1 represents a hydrogen atom or a methyl group, R2 represents a hydrogen atom, a halogen atom, a methyl group, a cyano group, a C1-C4 alkylthio group or a phenylthio group, R 7 and R 6 are hydrogen and R 3 is hydrogen or methoxy, or R 7 represents a hydrogen atom and R 5 and R 5 together form a bond, or R3 is hydrogen or methoxy and R7 and R8 together form a bond, R 1 represents a C 1 -C 4 hydrocarbon radical, R 5 represents a hydrogen atom, a C 1 -C 4 hydrocarbon radical or a phenyl group, X represents an oxygen atom, a sulfur atom or an imino group, W represents an oxygen atom or an imino group, A represents a radical of formula CHR 6, CH 2 -CHR 5 or CH = CR 6, wherein R 6 represents a hydrogen atom or a C 1 -C 4 alkyl group and n is a number of 0, 1 or 2, and pharmaceutically acceptable salts thereof, wherein the ergoline derivative of formula (II): wherein: R 1, R 2, R 5, R 6, R 7, R 6, A and n are as defined above, and B is cyano, C 2 -C 5 alkoxycarbonyl or carbamoyl condensed with a compound of formula III X = C = N = R 5 (III) wherein R 5 and X are as defined above, in water, ethanol, acetic acid or pyridine, at a temperature of 50 to 100 ° C and the resulting intermediate is cyclized either in the same condensation environment or after isolation by heating under a vacuum of 13 to 200 Pa to a temperature of 130 to 160 ° C, after which the optionally obtained product is converted into its pharmaceutically acceptable salt.