FR2508043A1 - ORALLY EFFICIENT APORPHINE DERIVATIVES AND METHOD OF MANUFACTURING THE SAME - Google Patents

Abstract

THE OBJECT OF THE INVENTION IS COMPOUNDS OF GENERAL FORMULA (CF DRAWING IN BOPI) IN WHICH R IS A GROUP LOWER ALKYL, LOWER ALKYL SUBSTITUTE, CYCLOALKYL, CYCLOALKYL SUBSTITUE, ALCENYL INFERIEUR, ALCENYL INFERIEUR, ALCENYLE SUBSTITUTE, ALCENYLE SUBSTITUTE, ALCENYLE SUBSTITUTE, ALCENYLERIECLE, SUBSTITURED ALKYLE lOWER, lOWER OR phenylalkenyl phenylalkynyl lOWER AND R AND R REPRESENT OR HYDROGEN GROUP Methyl, alkyl lOWER, lOWER aLKYL SUBSTITUTED cYCLOALKYL, cYCLOALKYL SUBSTITUTED aLKENYL lOWER, lOWER aLKENYL SUBSTITUTED, lower alkynyl, substituted lower alkynyl, pHENYLALKYL lOWER phenylalkenyl LOWER AND LOWER PHENYLALCYNYL AND R REPRESENTS HYDROGEN OR A HYDROXY, GOLD OR -OCR- GROUP

Description

Many derivatives of aporphine are endowed with

  Thus, aporphine (APO) and N-n-propylno-

  Apormorphin (NPA) have potent and selective effects on the central nervous system and other dopamine receptors These aporphin compounds have been used clinically, particularly in

  neurological and psychiatric disorders, but their use

  clinical trial was limited by their poor biological availability.

  and their short duration of action.

  According to the invention, an aporphin derivative which contains two hydroxyl groups on an aromatic ring and which has a therapeutic effect when it is administered subcutaneously or intraperitoneally can be converted into an effective therapeutic compound by orally by bridging the hydroxy groups to form a dioxy group such as, for example, methylenedioxy The dioxy group is dissociated in vivo to give the

  compound that carries the two neighboring hydroxyl groups.

  The therapeutic derivatives of aporphine, which have the following structure, are particularly interesting according to

  the invention and can be converted into a therapeutic composition.

  orally effective, which is dissociated in vivo in

  releasing the compound having the two adjacent hydroxy groups.

R 4 / -R

R 2 O /

  in vivo R 4 -R HO HO wherein R 1 is lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, lower alkynyl

  substituted, lower phenylalkyl, lower phenylalkenyl and phenyl

  lower alkynyl, R is a hydrogen atom or a hydroxy group, -O-R or -O-C-R 5 where R is methyl or lower alkyl and tg 5 O

  R 2 and R 3 represent hydrogen, a methyl group or R 1.

  The present invention is also generally applicable to dopamine agonists, which have two adjacent hydroxyl groups on an aromatic ring and which have dopamine agonist activity, when administered subcutaneously or inter-peritoneally. These compounds include not only the derivatives of aporphine, but also the compounds not belonging to the aporphine series, for example the compounds of the following structures: R 2 R 2

O X

(A) OH

  wherein R 1 and R 2 are hydrogen or methyl or lower alkyl

/ R 1

HO /, R 2

-I

HO ,, O

(B) H

  in which R 1 and R 2 represent hydrogen or a methyl or lower alkyl group HO

(C) HO

  in which R 1 and R 2 represent hydrogen or a methyl group

or lower alkyl.

  According to the invention, there are also described derivatives of aporphine which are effective orally

  in the treatment of neurological and psychiatric disorders.

  Also described are aporphin derivatives which are effective in the prevention and treatment of duodenal ulcers and

  may be administered orally or subcutaneously or peritoneally.

  Preferred examples of these new compounds and dioxy groups have the following structures of formulas

N-R 1 R 2 -C

2 R 3 -

  Compound Dioxy group wherein R 1 represents lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, lower phenylalkyl, phenyl

  lower alkenyl and lower phenylalkynyl and R and R represent

2 3

  ie hydrogen, methyl, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl,

  lower alkenyl, substituted lower alkenyl, lower alkynyl

  lower alkynyl, lower phenylalkyl, lower phenylalkenyl and lower phenylalkynyl, and their

  pharmaceutically acceptable acid addition salts.

  The Applicant has found in particular that (-) 10,11-methylenedioxy-N-n-propylnoraporphine is especially effective when administered orally in the prevention and treatment of duodenal ulcers and in the treatment of

  Psychiatric and Neurological Disorders The Applicant also

  It has been found that the methylenedioxy group is a particularly effective dioxy group. It is believed that the compounds of the invention are converted in vivo to the dihydroxy compound and are

  effective oral and long-acting.

  In the present description, the term "alkyl

  lower "saturated monovalent aliphatic radicals, including

  C 2 -C 6 branched chain and straight chain radicals,

  such as, for example, ethyl, propyl, isopropyl, butyl,

butyl, amyl or hexyl.

  The term "lower alkenyl" means monovalent C 3 -C 7 aliphatic radicals which contain at least one double bond and which are straight or branched chain, such that,

  for example 1- (2-propenyl), 1- (3-methyl-2-propenyl), 1- (1,3-

  dimethyl-2-propenyl) or 1- (2-hexenyl).

  The term "lower alkynyl" means the monovalent C 3 -C 7 aliphatic radicals which contain at least one triple bond and which are straight or branched chain, such as, for example 1- (2-propynyl), 1- (1-methyl) -2-propynyl), or

1- (2-heptynyl).

  By "cycloalkyl" is meant the aliphatic radicals

  cyclic C 3 -C 8 saturated ticks, such as, for example, cyclo-

  propyl, cyclobutyl, 2-methylcyclobutyl, cyclohexyl, 4-methyl-

cyclohexyl or cyclooctyl.

  By "phenyl-lower alkyl" is meant

  lower alkenyl "and" lower phenylalkynyl "monovalent radicals consisting of a phenyl ring bonded to the rest of the

  molecule, respectively, by a divalent radical lower alkylene

  C 1 -C 4, such as, for example, methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene, 1,2-propylene or 1,4-butylene; or by a divalent C 2 -C 4 lower alkynylene radical, such as, for example, 1,2-ethynylene, 1,3-propynylene, 1,3- (1-butynylene), etc. In addition, the benzene ring of these phenylalkyl radicals lower, lower phenylalkenyl and lower phenylalkynyl may be substituted by one or more substituents selected from lower alkyl, lower alkoxy, halo (chloro, bromo, iodo or fluoro), nitro, lower alkylmercapto, methylenedioxy and trifluoromethyl. Suitable acid addition salts are those derived from various acids, such as formic acid, acetic acid, isobutyric acid, α-mercaptopropionic acid, malic acid,

  fumaric acid, succinic acid, succinamic acid, tartaric acid

  triacetic acid, citric acid, lactic acid, benzoic acid, 4-methoxy

  benzoic acid, phthalic acid, anthranilic acid, 1-naphthalene

  carboxylic acid, cinnamic acid, cyclohexanecarboxylic acid, acid

  mandelic acid, tropic acid, crotonic acid, acetylene acid

  dicarboxylic acid, sorbic acid, 2-furancecarboxylic acid, cholic acid, pyrenecarboxylic acid, 2-pyridinecarboxylic acid, 3indoleacetic acid, quinic acid, sulfamic acid, methanesulfonic acid, benzenesulfinic acid, butylarsonic acid,

  p-toluenesulfonic acid, benzenesulfinic acid, butyl

  arsonic, diethylphosphinic acid, p-aminophenylarsinic acid,

  phenylsicylic acid, phenylphosphinic acid, methylphosphoric acid,

  Phenic acid, phenylphosphinic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrocyanic acid, phosphotungstic acid, molybdic acid, phosphomolybdic acid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid, barbituric acid, etc.

  Dopamine agonist activity.

  With regard to dopamine agonist activity, the compounds of the invention are tested in the rat stereotyped behavioral test according to the techniques described by Baldessarini, RJ, (Walton, KG and Borgman, RJ 1976), "Prolonged apomorphine-like behavioral effects

  of apomorphine esters "Neuropharmacology 15, page 471

  In some rats, the presence of Nn-propylnorapomorphine (NPA) in the frontal brain tissue after administration of (-) 10,11-methylenedioxy-Nn-propylnorapomorphine (MDO-NPA) is investigated by a specific high-performance liquid chromatographic method. with electrochemical detection (HPLC / ec) (Westerink, BH C and Horn AS 1979 "Do neuroleptics prevent the penetration of dopamine agonists into the brain" Eur J Pharmacol 58 page 39) The results obtained are shown in Table I below. The compounds according to the invention are very active in the induction in vivo of stereotyped behavior when they are

administered orally.

  MDO-NPA at doses of more than 2 rmol / kg i p. (about 0.68 mg / kg) produces increases in the overall dose-dependent motor activity, NPA and APO have very similar effects on motor activity, with increased counts at doses greater than 2 ymoles / kg, but no significant effect at lower doses On the contrary, MDONPA induces inhibition of locomotor activity at doses below 2 pmol / kg, with a maximum effect at 0.3 Pmol / kg (approximately 0.1 mg / kg) In addition, only MDO-NPA induces a strong catalepsy at doses similar to those which inhibit the general activity again with a maximal effect at 0.3 mol / kg ip (at NPA and APO produce only 15% and 7% stereotypy of MDO-NPA, respectively, N = 12) Thus, MDO-NPA has a clearly biphasic pattern of activity, in which low doses exert inhibitory effects on motor activity and significant cataleptic effects resembling those of a neurolept while higher doses exert excitatory and stereotyped behaviors as expected from a dopamine agonist (DA)

  conventional such as APO (apomorphine) or NPA (N-n-propylnoraporphine).

  The duration of effects on the stereotyped behavior of MD 0-NPA exceeds that of NPA at doses greater than 1 mole / kg ip and MDO-NPA shows a consistent increase in duration of action with increased dose The duration of the behavioral action of NPA is about equal to or slightly better than that of APO, but both NPA and APO have a tendency to increase duration with a lower dose.

than that of the MDO-NPA.

  When studying other derivatives of NPA or APO, with substituents such as methylene carbon or

25080-43

  an electron withdrawing group such as a nitro function, in

  position 8, MDO-APO has excitatory effects that are not

  tants at a high dose (10 mg / kg i p) and no noticeable effects on behavior after oral administration (1 to 5 mg / kg), Measurement of biological activity. Male Sprague-Dawley rats (provided by Charles River Laboratories) initially weighing 175-200 g are placed, four per cage, with free access to food and

  under controlled exposure (7 am to 7 pm) at constant temperature

  aunt 21-23 C and humidity controlled (40-50%) The aporphins as described below are administered freshly dissolved in the acid.

  citric acid 1 m M mixed with 0.9% w / v physiological serum

  (1: 4 by volume); this solvent is also used as

  vehicle ("placebo") by the control test.

  peridol in the same medium; 2diethylaminoethyl 2,2-diphenylvalerate hydrochloride (SKF-525A) is administered in physiological saline. Locomotor activity is evaluated using an electronic printer activity control apparatus (EAM from Stoelting Co., Chicago, IL) within a sound-insulating chamber, typically for minutes, as described. previously (Stewart, Campbell, Sperk and Baldessarini, 1979, Psychopharmacology 60, pp. 281-289;

  and Baldessarini, 1981a, Psychopharmacology 73, pages 219-222.

  Stereotyped behavior is assessed by observing

  Trained, according to a scoring-scale method previously described (Campbell and Baldessarini, 1981a) In summary, the ratings are as follows: O, no stereotypy, normal locomotion; 1 discontinuous sniffing, reduced locomotion; 2 continuous sniffing, periodic exploration only; 3 continuous sniffing, mouth movements, infrequent exploratory activity Notations are done every 10 min per observation for 30 s, typically for a duration of 60 min (maximum score "18, O / h). determined as described in detail elsewhere (Campbell and Baldessarini, 1981a, 1981b, Life Sciences 29, pp. 1341-1346) In summary, rats are evaluated every 10 min by timing the maintenance of an abnormal position with the legs of front on a steel bar 1 cm in diameter placed parallel to the bench and 8 cm above, so that the rat rests only on its hind legs It takes as a maximum duration of 60 S and almost all normal untreated rats remain on the bar for less than 5 s The scores are made according to the following scale: O, support on the bar for 0-10 s; 1, 10-29 s; 2, 30-59 s ; 3, duration, e 60 * So, in a typical session of 6 0 min, the maximum notation

is 18.0.

  In all experiments, except those evaluating the time course of the effects of the drug, the rats are given an injection of the vehicle and then left to rest.

  for 15 minutes to adapt to non-specific stimulation effects.

  before a second injection of the tested agent (or placebo) and the immediate behavioral study. Behavioral data are evaluated by Student's t-test and always expressed in

mean + standard deviation.

  The following tables illustrate the data used to evaluate the compounds according to the invention in their dopamine agonist activity. In Table I, the route of administration and stereotyped behavior for MDO-NPA and Other Aporphines Table II shows the effects of the microsomal oxidase inhibitor on the low and high dose effects of MDO-NPA effects. Table LII evaluates the effects of

  haloperidol on stereotyped behavior induces MDO-NPA.

  Table IV compares the characteristics of the NPA and the MDO-NPA. In Table V, the MDO-NPA is compared with the

  similarities in stereotypical behavior and activity.

locomotory life.

Antiulcerogenic activity.

  It has been shown that duodenal ulcers induced

  rats with cysteamine or propionitrile are suitable models.

  to study the pathogenesis of acute and chronic ulcer

  duodenum and for the test of the therapeutic effect of medicinal

  Antiulcer Preliminary structure-activity studies, pharmacological and biochemical studies in the applicant's laboratories have suggested that catecholamines, especially dopamine, are involved in the pathogenesis of the experimental duodenal ulcer in rats. Incidence and intensity of duodenal ulcer induced by cysteamine has been demonstrated by the administration of agonists or antagonists

  Dopamine dopamine agonists (eg bromine

  criptine or lergotrile) administered either pre-treatment or post-treatment, decrease the intensity of acute and chronic duodenal ulcers and decrease the flow of gastric acid

  in rats given cysteamine or propionitrile.

  Chemically induced duodenal ration is associated with changes in the sensitivity and number of dopamine receptors in the gastric mucosa and duodenal mucosa and in the muscularis propria. Pharmacological limitations of potent agonists

  available dopamine, such as apomorphine and N-n-

  propylaporphine (NPA) are in particular a short duration of action and poor oral bioavailability.

  discovered according to the invention that (-) 10,11-methylenedioxy-N-n-

  propylnoraporphine (MDO-NPA) is a unique oral and long-acting effective aporphine derivative that appears to act as a precursor to NPA by exerting its activity on

  dopamine receptors in the brain.

  In cysteamine-treated rats, MDO-NPA causes significant inhibition of experimental duodenal ulcers Cysteamine-induced acute duodenal ulcers are virtually eliminated by MDONPA following a time and dose-dependent response: a single high dose, either

  MD 0-NPA, or NPA, is active, whereas a daily treatment

  bind in small amounts virtually eliminates ulcers

  Cysteamine-induced duodenal (+) - butaclamol, antago-

  Dopamine, aggravates experimental duodenal ulcers

  and reverses the beneficial effect of NPA and MDO-NPA.

  MDO-NPA, a dopamine agonist, appears to exert a strong duodenal anti-leukogenic effect. Its action is approximately one-fold more potent than that of cimetidine, a histamine H 2 -receptor antagonist 10-fold more active than other dopamine agonists ( for example, bromocriptine, lergotrile), and its potency is identical to that of natural protaglandins that also inhibit this experimental duodenal ulcer.

  MDO-NPA is a drug precursor with effective activity

  oral and prolonged storage on dopamine receptors (eg in the duodenum and / or the brain) The drug or one of its analogues may also be of clinical interest

  for the prevention and / or treatment of duodenal ulcer.

  As Table VI and VII below indicate,

  Oral MDO-NPA reduces the incidence and inten-

  of duodenal ulcers and gastric acid flow.

  With regard to the duodenal antiulcerogenic activity

  (-) - 10,11-methylenedioxy-Nn-propylnoraporphine, MDO-NPA is administered once daily for 7 days to rats prior to administration of cysteamine hydrochloride which induces duodenal ulcers. 50 or 100 micrograms per

  g body weight are effective at preventing ulcers.

  This dose is much lower than that of any other known anti-ulcer compound which usually requires at least 0.2 mg per

100 g body weight

  The following examples illustrate the invention without

however, limit its scope.

EXAMPLE 1

  Synthesis of (-) - 10,11 l-methylenedioxy-N-n-propyl hydrochloride

  noraporphine (MDO-NPA) A solution of 2.0 g of (-) Nn-propylnorapomor Phine hydrochloride (NPA) in 16 ml of dimethylsulfoxide (DMSO) and aqueous sodium hydroxide (0.8 g in 8 ml of water) with 1.2 g of methylene bromide under a nitrogen atmosphere The resulting mixture is stirred for 4 hours at 80 ° C., cooled and poured into ice water. The precipitate thus obtained is filtered, dried and extracted. The evaporation of the dried extract gives the crude product which is purified by column chromatography using silica gel and a mixture of ethyl acetate-methylene chloride (1:10). volume) as eluent The free base thus obtained is converted into hydrochloride by ethereal HC 1 to obtain 0.75 g (36% yield) of the product; F 245-250 C (decomposition);

  mass spectrum M + 307; lal 546 = -49.55 (c = 0.44 g in MeOH).

  Elemental analysis gives: C 99.7%; H, 103.4%; N 97.3% of the expected values calculated for C 20 H 21 NO 2, H Cl This compound is the one used

in the evaluation of the MDO-NPA.

EXAMPLE 2

  Synthesis of (-) - 10, 11-methylenedioxy-N-n-propylnorapomorphine

(MDO-NPA) from codeine.

  The synthesis steps are illustrated by the following diagram

OH OH O

-CHN

o CH 3 o A CH x, 2 CH

CHO XCH 3 CH 3

CCH 3

(A) (B) (C)

N N

CH C CH

H 2 '2,' 2

O1 N CH OH N H 2 * - H 2

CH-O H 3 OH CH 3 CH 3

2 O

(D) (E) (F)

  The first step, that of N-demethylation of codeine (A) to norcodecine (B), is well known in the art and can be carried out in various ways. The procedure described by GA Brine, KG can be advantageously used. Bolt, C King Hart and FI Carroll in Organic Preparations and Procedures Int 8 (3), pp. 103-106 (1976). This uses methyl chloroformate to form the methylcarbamate of (A) intermediate and

  then hydrazine to dissociate the carbamate of norcodine (B).

  The alkylation of norcodine to produce compound (C) can be carried out with n-propyl chloride, bromide, iodide, p-toluenesulfonate, etc. It can be carried out in a variety of suitable solvents, including alcohols, such as methanol, ethanol, propanol, methoxyethanol, etc. Bases can be added such as pyridine, sodium carbonate

  or potassium or magnesium oxide as the acid acceptor.

  By way of illustration, n-propyl iodide is used with ethanol as solvent in the presence of anhydrous potassium carbonate. The N-npropyl derivative (C) is obtained in quantitative yield. The rearrangement of N-n-propylnorapocodeine can be carried out by treatment with various strong acids, such as the usual inorganic acids, for example sulfuric and hydrochloric acids, or with sulphonic acids, such as

  methanesulfonic acid or p-toluenesulfonic acid.

  The use of methanesulfonic acid as both a solvent and a reagent is a suitable procedure and can give very high yields of apodecan derivative.

  according to the invention, compound D can be obtained with yields of

up to 98%.

  The demethylation of the compound D can be carried out by the use of reagents, such as aqueous hydrobromic acid & 48%, hydrobromic acid in acetic acid, trichloride or boron tribromide, etc. The best results are obtained with boron tribromide, with both superior yields (78%) and superior product quality.

  boron tribromide in various solvents, but chlorine

  form, chlorobenzene or methylene chloride The reaction

  requires only a short duration of 15-60 min at 0-20 C.

  The final step, that of the formation of a methylene bridge between the two phenolic hydroxyls, can be carried out with methylene chloride, bromide or iodide.

  aprotic dipolar solvents, such as dimethylformat-

  mide, N-methylpyrrolidone or dimethylsulfoxide In the example below> a phase transfer method is used, with

  methylene bromide, in the presence of alkali and with an ammonium salt

  quaternary nium as a catalyst The method was first applied to catechol by A P Bashall and J F Collins

  in Tetrahedron Letters, No. 40, pp. 3489-3490 (1975).

  The reaction takes place at about 1000 ° C. and is complete in 2 hours. The desired compound F is obtained with a yield of 80%.

  use as quaternary ammonium salt tetra-n-bromide

  butylammonium, benzyltrimethylammonium bromide or a chloro-

  mixed methyltrialkylammonium mercury sold under the name "Adogen 464". Examples of the preparation of compounds C, D, E and F are described below. Compound C A mixture of 19.3 g (0.0678 mol) of norcodine, 13.3 g (0.078 g) is stirred under reflux for 25 hours. mole) of n-propyl iodide, 11.74 g (0.085 mol) of anhydrous potassium carbonate and 150 ml of 95% ethanol 300 ml of water are added, the solution is extracted with four portions of chloroform, 150 ml, then 3 x 100 ml,

  and the extracts are dried over anhydrous magnesium sulfate.

  to dryness gives 22.15 g (100% yield 7) of N-n-propylno-

  codeine in the form of a clear oil which gives a single spot Rf V 0.7 in thin layer chromatography (silica with

CHCl 3 / CH 3 OR 10: 1).

  Compound D 22.15 g (0.0678 moles) of N-npropylnorcodine are dissolved in heating in 120 ml of methanesulphonic acid and the mixture is stirred under a nitrogen atmosphere at 90 ° -950 ° C. (internal temperature) for 1 hour. cool the solution and dilute it by

  320 ml of water, then neutralized at pH 11 with ammonium hydroxide

  concentrated by stirring and cooling It precipitates a solid which is filtered, washed with water and dried under vacuum

  at 40 C until constant weight It oozes at 127 C then melts and

  185 C Thin layer chromatography (silica with CHCl 3 / CH 3 H 2: 20: 1) gives a green spot, Rf 0.9 20.44 g is obtained

  of the product (yield 97.8% of theory).

  When a too rapid addition causes the precipitation

  In the form of an oil, the oil is extracted with chloroform

  and the chloroform is stirred several times with successive portions.

  soda solution until the disappearance of

  all of the low Rf substance observed on the chromatographic plate

thin layer graph.

2508.043

  The hydrochloride is formed quantitatively by

  addition of an ethereal solution of hydrogen chloride to a solution

  chloroformic base It oozes at 203 ° C and melts at 215-222 ° C.

  Compound E is added dropwise, under a nitrogen atmosphere,

  a solution of 2.0 g (0.05% mole) of N-n-propyl hydrochloride

  norapocodeine in 15 ml of methylene chloride to 17.4 ml of a 1M solution (0.00174 mol 3 equivalents) of boron tribromide, stirred at 5 ° C., in 10 min. The cooling is stopped and stirring is continued at The solution was decanted from a small amount of precipitated tar and 3.0 ml of methanol was added slowly with stirring.

  an excess of anhydrous ether until the precipitation is complete.

  The mixture was maintained at 0 ° C for one hour, the precipitate was filtered and dried in vacuo to constant weight to give 1.70 g (78.0% of theory) of Nn-propylnoromorphomorphine hydrobromide as a solid. colorless, F 270 C after seepage at 260 ° C. Thin layer chromatography on silica in CHCl 3 / CH 3 H 7: 1

gives a single spot at Rf 0.7.

  Compound FA a mixture of 6.9 g (0.04 mol) of dibromomethane, 1 ml of water and 0.12 g (0.00026 mol) of Adogen 464, vigorously stirred and refluxed under nitrogen, slowly add in 2 hours

  a solution of 10.0 g (0.0265 mole) of N-n-propyl-norapomorphine hydrobromide in 12.5 ml of water and 7.4 g of a sodium hydroxide solution.

  50% sodium When the addition is complete, the reaction mixture is stirred and refluxed for a further 1 hour. After cooling, 10 ml of methylene chloride are added, the solution is dried over magnesium sulphate and adsorbed on a column of silica gel. Elution with methylene chloride gives the desired product. Ethereal hydrogen to the main fraction of the eluate until precipitation is complete. Vacuum drying gives 8.23 g (80.0%

  the theory) of methylenedioxy-N-n-propylnorapomor hydrochloride

  phine as a colorless solid; F 251-253O C.

EXAMPLE 3

  Synthesis of (-) 8-nitro-10,11-methylenedioxy-N-n-hydrochloride

  propylnoraporphine (8-nitro-IDO-NPA).

  80 mg of NDO-NPA are added in small portions to 10 ml of 60% by volume nitric acid with stirring. After 15 minutes,

  a clear solution is formed and stirred overnight.

  The reaction mixture is neutralized with 4% w / v aqueous NaOH and extracted with ether. The ether extract is washed with water, dried over Ca SO 4, filtered and evaporated to dryness. 4, the free hydrochloride base by addition of ethereal HC 1 to give mg (55%) of the product; F 225-229 C; mass spectrum M 352, 351 (M + -1); 323 (M + C 2 H 5); 277 (323-NO 2) Elemental analysis gives: C 100.3%; H, 102.8%; N 100.1% of the expected values for

H 20 N 204 'C

EXAMPLE 4

  (-) 10,11-heptylidene-2-dioxy-N-n-propylnorapor-hydrochloride

phine (methyl-pentyl-MDO-NPA).

  A mixture of 1.0 g of NPA and 1.0 g of heptanone-2 is treated with 1.0 g of P 205 at 25 ° C. and then heated at 110 ° C. for 2 hours. overnight at room temperature The solid is added to a solution of Na 2 CO 3 at 10% w / v, stirred and extracted with ether. The ethereal extract is dried over Ca SO 4, filtered and evaporated. to dryness The crude product is chromatographed using silica gel and ether / hexane (1: 2 by volume) as eluent to obtain 300 mg (26% yield) of the base. The free base is converted to the hydrochloride by the addition of HC 1 ethereal

  k an ethereal solution of the base F 120-125 C The elemental analysis

  give: C 100.1%; H 103.9%; N 98.5% of expected values for C 26 H 32 NO 2 C.

EXAMPLE 5

  (-) 11-Butylidene-2-dioxy-N-n-propylnoraporphine hydrochloride

(methyl-ethyl-MDO-NPA).

  This compound is similarly prepared from 1.0 g of NPA and 0.8 g of methyl ethyl ketone to give 200 mg (17% yield) of the product; F 150-156 C Elemental analysis gives: C 100.4%; H, 101.2%; N 95.0% of the expected values calculated for

H 20 N 203 'HC.

TABLE I

  Route of administration and response typed at DO-NPA and other aporphrnes.

  Stereotype score Effect duration (min) Fa Data are mean standard deviation (t) values for N = 6 rats per group receiving doses of each aporphine (1 mg / kg or approximately 3 pmol / kg) by intubation orogastric (po) or by subcutaneous (sc) or intraperitoneal injection (ip) Stereotypy is noted for 1 hour as described in the methods chapter and the duration is defined as completed when the scores fall to i 3 (on a

maximum possible of 18).

* ## STR2 ## Agent (1mg / kg) P o s C i p p o s C i p.

  MD 0-NPA 17.0 + 1.2 17.5 + 0.4 16.5 + 0.8 112 + 20 106 + 10 116 + 12

  NPA O 17.5 + 0.8 17.5 + 1.0 O 72 + 6 70 + 10

  APO O 17.5 + 0.4 16.5 + 2.4 O 70 + 5 72 + 12

T A B L E A U II

  Effects of the microsomal oxidase inhibitor (SKF-525 A) on the effects of low and high doses

MD 0-NPA on the behavior.

  F 4 Data are mean values + standard deviation (N = 4 to 8 rats per state) Animals are pretreated with 40 mg / kg SKF-525 A, ip, or vehicle 30 min before MDO-NPA (in the doses noted, from 0 to 3 mg / kg, ip) The activity is then recorded electronically for 1 h after the low doses of MDO-NPA (data in meters / hour), or the stereotypy is noted every 10 min. for 1 hour after higher doses ND means "not determined" Asterisk indicates significant difference in t-test between control rats and rats pretreated with the oxidase inhibitor (p 4 0.01) In one control test, the rats are pretreated with 40 mg / kg of SKF-525 A ip or its vehicle (N = 6) as described and then administered 3 mg / kg, ip, of NPA; the resulting notes of stereotypy are from

  17.4 + 0.2 for the control rats against 17.0 + 0.3 for the rats treated with the oxidase inhibitor, respec-

  This indicates that there is no significant effect of the drug on NPA actions itself.

  Dose of MDO-NPA Control SKF-525 A (mg / kg) Activity Stereotypy Activity Stereotypy

0 409 + 36 O 422 + 28 O

0.05 190 + 20 ND 425 + 40 * ND

0.10 130 + 30 ND 415 + 29 * ND

0.20 260 + 33 ND 410 + 32 * ND

  0.30 435 + 29 12.8 + 0.6 440 + 38 1.7 + 0.6 *

1.0 ND 16.5 + 0.1 ND 0.8 + 0.2 *

3.0 ND 16.2 + 0.9 ND 0.8 + 0.5 *

i Ul Ln Co c't oo O O

TABLE III

  Effects of haloperidol on MDONPA -o stereotyped behavior Haloperidol or its vehicle is administered 30 min before MDONPA (both dissolved in the same citric acid-saline vehicle) Stereotypy is noted for 60 min as

  described in the methods chapter Data are averages + standard deviation (stoichiometric

  typie, when 18 = maximum in 1 h) for N 6 rats per group; the asterix indicates p <0.0001

in the test t.

  M OH O Haloperidol (mg / kg) MDO-NPA (mg / kg)

0.3 1.0

0 11.6 + 0.8 16.6 + 0.4

0.3 0.3 + 0.2 * 0.5 + 0.2 *

1.0 0.3 + 0.2 * 0.2 + 0.4 *

WATER IV

  Characteristics of NPA and MDO-NPA The data are for the stimulation of IP in striatal homogenisates at

  the rat; inhibition of HlAPO binding to synaptic membranes

  soaneles of the caudate beef core; stereotypy notes (maximum pos-

  sible = 18.0); and brain levels of NPA by HPLC / ec; (*) p Z 0.01.

Feature

X (N)

  Stimulation of adenylate cyclase (c AMP, pmoles / determination) Control (no addition)

NPA (50, PM)

IIDO-NPA (100 y 1 M)

(1000 PM)

  IC 5 against the fixation of l 3 JAPO (nil) NPA

IIDO-NPA

  Stereotypy note for 30 min after MDO-NPA (1 mg / kg) i.p. P.O. Cerebral NPA (ng / g) 30 min after MDO-NPA (1 mg / kg) i.p. P.O. 2, -38, 67 2, 92 2.06 t 0, 14 t 0, 28 t 0.32 f 0.3, 3 C 2.5 t <0.2

850 + / 85

* (8)

(4) i (4) (3) (3)

16.5 + 1.2 (5)

, 5 t 1, 6 (5)

6.0 + 0.8 (3)

3, 3 + 1, 8 (3) _

T A B L E A U V

  Effects of MDA-NPA analogues on stereotyped behavior and locomotor activity.

  Substituents R R Stereotypy Locomotion

  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 2 R 3

  8-nitro-MDO-NPA CH 3 (Cl 2) 2 H H 4.4 + 2.5 74.4 + 9.8 Methylethyl-MDO-NPA CH (H 2) CH 3 O 2 31.5.1 t N

H 3 (C 122 CH 3 32

  Methylpentyl-MDO-NPA CH 3 (CH 2) 2 CH 3 CH 3 (CH 2) 4 11.1 + 5.7 86.1 22.3 The data are mean + values (N 3 to 6 rats per condition ) for the effects of seven aporphine derivatives (R = substituents, attached to the structure above) Complete chemical names for all compounds are given in the Methods chapter Ratings are expressed in percent of the maximum possible score (100% = 18.0) stereotypy (controls receiving the placebo injection give

  grades of 4.4 and 2.5%); and in percent of the locomotor activity of the controls (100% = 430 86 counts / h).

  The data are for a dose of 10 mg / kg (i p) although the doses of 1 and 5 mg / kg are also tested.

  (*) MDO-APO gives a significant effect (p 4 0.01 in test t) to inhibit locomotor activity

  at 10 mg / kg i p, but it induces a weak and inconsistent stereotypy (not statistically significant).

  cant); the methyl-ethyl-substituted analog of MDO-NPA has a weak stereotypic activity, whose onset is delayed by about 30 min and lasts about 60 min.

ND = not determined.

u L Co (N oo o A

TABABLE VI

  Effect of MDO-NPA or NP 'on cysteamine-induced NPA rat duodenum ulcer

  Duodenal ulcer Group Pretreatment Doaslèe doéa Pretreatment group l Doae Incidence Intensity __________ (p (pg / 100 g) (Positive / total) (Scale: 0-3) 1 Control 10/12 1,8

2 MDO-NPA 50 4/6 0.8

3 "100 3/6 0.5

4 Postcode 50 2/9 1,1

"100 6/9 0.9 '

  The groups consist of 3-4 Sprague-Dawley rats (160-180 g). Each experiment is repeated at least two

  The results of these groups are reported together. Dopamine agonists are injected subcutaneously

  dermal, once daily for 7 days prior to administration of cysteamine hydrochloride (manufactured by Aldrich) at 28 mg / 100 gpo three times at 3 h intervals. Animals are sacrificed 48 h after duodenal ulcerogen, On evaluates the intensity of duodenal ulcer on a scale from 0 to 3, in which O = no ulcer, 1 = superficial mucosal erosion, 2 = transmural necrosis, deep ulcer, 3 = perforated duodenum ulcer or penetrated In Table VI, the MDO-NPA is transformed

  in vivo in NPA, for example N-n-propylnorapomorphine.

  r J Ln Co u, I C> w. F Effect of Pretreatment Group (A) I Control II MDO-NPA (0-1 mg gx 1 d) III IDO-NPA (o, 1 mg gx 1 week) IDO-NPA on Initial Flow (B) 187 -k 20

I 47 + 13 ***

I 120 - 36

TABLE

acid flow 1 h 2 h

68 -k 17 195 -

28 + 18 66 +

29 + lo 66 +

E TO VII

  Gastric induced by ystysamine.

  3 h 4 h 5 h 6 h 7 h Total flow (Eq> 48 141 32110 25 104 18 91 + 12 99 l 0 1043 102 29 81 + 40 17 8 * 10 + 3 ft 20 + l Il ** 18 + 6 * ** 288 + 67 *** 21 * 36 -k 9 * 14 6 ** 17 -k 7 ** 18k 14 ** 9 4 *** 306 62 *** (A) In addition, rats of all the groups receive cysteamine hydrochloride, 15 mg / 100 gpox 1.30 min

  after the last dose of MD 0-NPA.

  (B) At the opening of the gastric fistude.

  * = p <0.09; ** = p <0.01; *** = P <0.001 M-1 Co (M t N)

Claims (12)

R E V E N D I C A T IO N S   1 Derivatives of aporphine, characterized in that they correspond to the general formula -R R 3 <   in which R1 is lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenoyl,   substituted lower alkenyl, lower alkynyl, lower alkynyl   substituted phenylalkyl, lower phenylalkenyl or lower phenylalkynyl and R 2 and R 3 are hydrogen or methyl, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, lower alkynyl substituted, lower phenylalkyl, lower phenylalkenyl and lower phenylalkynyl and their acid addition salts acceptable in pharmacy.   Compounds according to claim 1, characterized   in that they consist of (-) 10,11-methylenedioxy-N-n-propyl-   noraporphine and its pharmaceutically acceptable acid addition salts. 3 New drugs, useful especially-as dopamine agonists, characterized in that they meet the general formula R 4 R N-R 1 R O   in which R 1 is lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl,   substituted lower alkenyl, lower alkynyl, lower alkynyl   substituted phenylalkyl, lower phenylalkynyl or lower phenylalkynyl and R 2 and R 3 are hydrogen or methyl, lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, lower alkynyl   substituted, lower phenylalkyl, lower phenylalkenyl and phenyl   lower alkynyl, and R 4 represents hydrogen or a hydroxy group,   Or R 5 is methyl or lower alkyl.   O 4 Therapeutic compositions, characterized   in that they contain at least one medicinal product according to the claim   3, in combination with a pharmaceutically acceptable carrier.   Process for the preparation of a compound of the general formula N-R 1 NR 1   in which R 1 is a C 1 -C 6 alkyl group, characterized in that it comprises the N-demethylation of codeine to norcodéine, the alkylation of norcodéiand to form the N-alkyl derivative, the   rearrangement with a strong acid to give 10-methoxy-11-   hydroxy-N-alkyl-norapomorphine, demethylation to give the, 11dihydroxy-N-alkyl-norapomorphine, and formation of the bridge   11-methylenedioxy by reaction with a methylene halide.   Process according to Claim 5 for the preparation of 10,11-methylenedioxy-N-propylnorapomorphine, characterized in that it comprises the N-demethylation of codeine to norcodéine, the alkylation of norcodéine to give the Nn-propyl derivative , strong acid rearrangement to form methoxy-11-hydroxy-Nn-propyl-norapomrorphine, demethylation to form 10,11-dihydroxy-Nn-propylnorapomorphine, and formation of the 10,11-methylenedioxy bridge. by reaction with a halide methylene.   Process for converting an aporphin derivative having 2 hydroxyl groups into neighboring positions on an aromatic ring   and therapeutically active when administered subcutaneously   cutaneous or intraperitoneal in an effective form orally, characterized in that is introduced into said compound a dioxy bridging group which is dissociable in vivo to give the derivative   of aporphine having the 2 neighboring hydroxy groups.   Process according to claim 7, characterized in that said aporphine derivative corresponds to the general formula R   Wherein R 1 is lower alkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl, alkenyl   lower, substituted lower alkenyl, lower alkynyl, aley-   substituted lower nyl, lower phenylalkyl, lower phenylalkenyl or lower phenylalkynyl and R 4 represents hydrogen or a hydroxy group, -O-R or -O-C-R wherein R is a group O methyl or lower alkyl.   A process for converting a dopamine agonist having 2 hydroxy groups into adjacent positions on an aromatic ring and having dopamine agonist activity when administered subcutaneously or intraperitoneally to an orally effective form, characterized in that a dioxy bridging group is introduced into said compound which is dissociable in vivo to give the dopamine agonist having the 2 neighboring hydroxyl groups.   Process according to claim 7, 8 or 9, characterized   in that the dioxy group has the following structure: R 2 c R 0-   in which R 2 and R 3 represent hydrogen or a methyl group,   lower alkyl, substituted lower alkyl, cycloalkyl, cycloalkyl   substituted alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, lower phenylalkyl, lower phenylalkenyl or lower phenylalkynyl.   The method of claim 7, 8 or 9, characterized   in that the dioxy group has the following structure: O-CH 2 O-   12 Derivatives of aporphine, characterized in that they are manufactured by the process according to claim 7, 8, 9, 10 or 11.   Compound according to Claim 12, characterized in that the dioxy group has the following structure: R 2 C, -0- R 2 R 3 'O-   in which R 2 and R 3 represent hydrogen or a methyl group,   lower alkyl, substituted lower alkyl, cycloalkyl, cycloalkyl   substituted alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, phenylalkyl   lower, lower phenylalkenyl or lower phenylalkynyl.   Compounds according to claim 12, characterized in that the dioxy group has the following structure: CH 2 O '   20. New drugs, useful in particular for the prevention and treatment of duodenum ulcer, characterized in that they correspond to the general formula HO HO in which R 1 is a lower alkyl, substituted lower alkyl, cycloalkyl or cycloalkyl group. substitute, lower alkenyl, lower substituted alkenyl, lower alkynyl, lower alkynyl   substituted, lower phenylalkyl, lower phenylalkenyl or phenyl-   lower alkynyl. Medicament according to claim 15, characterized   in that R 1 is n-propyl.