US3879554A - Use of 1,6-dimethyl-8-{62 -(5-bromonicotinoyloxymethyl)-10 {60 -methoxyergoline in treating cerebral and peripheral metabolic vascular disorders - Google Patents
Use of 1,6-dimethyl-8-{62 -(5-bromonicotinoyloxymethyl)-10 {60 -methoxyergoline in treating cerebral and peripheral metabolic vascular disorders Download PDFInfo
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- US3879554A US3879554A US347342A US34734273A US3879554A US 3879554 A US3879554 A US 3879554A US 347342 A US347342 A US 347342A US 34734273 A US34734273 A US 34734273A US 3879554 A US3879554 A US 3879554A
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- Prior art keywords
- cerebral
- nicergoline
- dimethyl
- methoxyergoline
- peripheral
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- ADYPXRFPBQGGAH-WVVAGBSPSA-N dihydroergotoxine Chemical compound CS(O)(=O)=O.C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2C(C=3C=CC=C4NC=C(C=34)C2)C1)C)C1=CC=CC=C1 ADYPXRFPBQGGAH-WVVAGBSPSA-N 0.000 description 1
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- RHGUXDUPXYFCTE-ZWNOBZJWSA-N ergoline Chemical group C1=CC([C@@H]2[C@H](NCCC2)C2)=C3C2=CNC3=C1 RHGUXDUPXYFCTE-ZWNOBZJWSA-N 0.000 description 1
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- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
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- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
Definitions
- the present invention has among its objects new pro- R R 'esses for using l-methyI-lumilysergol-lO-methylether $222 hmmg l 4 StCIS 0f the formula: R: is selected from the group consisting of 40 hydrogen and of a radical of:
- the process allows one to obtain the important intermediate I from commercial monohydrate lysergic acid.
- This intermediate l. according to the process of the above-mentioned U.S. Pat. No. 3.228.943. is transformed into the useful end products [1].
- the methylation step may be performed before or after the irradiation step with U.V. light in order to obtain the useful ergoline end products lll having a methyl group attached to the nitrogen atom in position 1.
- the methylation step may be carried out by reacting the nonmethylated ergolines in position 1 with methyl iodide in liquid ammonia in the presence of potassium amide.
- the potassium amide is produced in the same reaction solution by dissolving metallic potassium in liquid ammonia and this solution is oxidized by treatment with ferric nitrate. Afterwards. the lumilysergol-IO- methylether ester is added to a liquid ammonia solution which is treated with methyl iodide. The mixture is allowed to react for a period of from 1 to 2 hours and at a temperature of from 60 to 30C. It is preferable, to use a slight excess of potassium amide and methyl iodide.
- the ammonia is evaporated and the residue is taken up with crushed ice and an organic solvent immiscible with water, such as chlo- CH O-CO -R Methylation ICH liq NH K roform.
- the desired product is contained in the organic layer.
- the mixture is evaporated in vacuo to dryness and the residue is recrystallized from a suitable solvent selected from the group consisting of esters and lower aliphatic ketones such as ethyl ether and acetone.
- Nicergoline 1.6-dimethyl-8 beta- (5-bromonicotinoyl-oxymethyl l 0 alpha-methoxyergoline. which is called Nicergoline, is a new drug which displays valuable activity on cerebral and peripheral metabolic-vascular disorders.
- PHARMACOLOGICAL PROPERTIES of Nicergoline Nicergoline antagonizes the effects of exogenous and endogenous eatecholamines on adrenergic receptors because of its alpha-adrenoceptor blocking activity.
- the drug possesses a marked myorelaxant action on vessel walls. at the level of musculo-cutaneous vascular districts of the limbs as well as of the exoand endocranial vessels. which causes an increase in the arterial blood flow. Peripheral vasodilatation takes place at doses which do not significantly affect the splanchnic blood flow or the most important cardiovascular parameters (systemic arterial blood pressure. heart rate. cardiac output).
- Nicergoline does not modify the hypertensive effects due to stimu lation of hypothalamic and bulbar centers. Nicergoline clearly differs from the ergot alkaloids in that it does not cause vasoconstriction and does not have any emetic effect. even at high doses.
- the drug exerts a specific antagonist action on focal cardiac necroses caused by phenylephrine.
- Nicergoline causes an increase in the uptake of cerebral glucose and of cerebral 0 as well as a stimulation of brain metabolizing activity. It also acts on the energy state of the brain by favoring the conversion of adenylates into higher energy forms.
- Cerebral functions are positively influenced by Nicergoline as shown by a faster recovery of EEG patterns and evoked cortical potantials in ischemic brains of cats treated with the drug. Simultaneously with the effect on the restoration of the cerebral function. a restoration of the ATPase activity of nervous cells occurs as has been revealed by biochemical examinations.
- Nicergoline causes an accumulation of cyclic AMP in the brain only. probably in connection with its stimulating action on adenylcyclase or with its blocking action of phosphodiesterase in this tissue.
- Nicergoline affects the cerebral hemodynamics by decreasing vascular resistance and by increasing blood flow. while it does not interfere with the autoregulation of cerebral vessels.
- the effects of the drug on metabolism and on cerebral flow in animals are further confirmed by both direct and indirect results of studies carried out in man.
- Nicergoline causes an increase of muscular activity. as shown by a higher resistance to muscular fatigue in the mouse.
- Nicergoline is able to inhibit the induced platelet aggregation.
- PHARMACOKINETICS A comparative examination of the results obtained by Nicergoline in rats. in monkeys and in man with radioactive compounds. indicates that Nicergoline is rapidly absorbed both by the subcutaneous and the oral route with large amounts being found in the liver and in the kidney. While it rapidly disappears from the liver. where it is probably metabolized. high concentrations remain in the kidney which is the main excretory route of the metabolites of the drug. Nicergoline is fully metabolized and most of its metabolites have been identified.
- EEG electroencephalograms
- Nicergoline activity at the level of the brain under pathological conditions of a metabolic-vascular origin. where it acts with a multiple mechanism of action. In these cases. the drug causes stimulation of the metabolism of nervous cells and an increase of cerebral blood flow.
- Obliterative and functional peripheral arteriopathies of various nature represent another field of clinical employment of Nicergoline. In this field. a clear increase in the peripheral blood flow was evidenced by trials performed with radioisotope clearance. rheography. plethysmography. morpho-oscillography and cutaneous thermometry.
- Clinical therapeutic results were represented by an improvement of the muscle-cutaneous blood flow. an improvement of trophic lesions. a decrease in hypersensitivity to cold and the reduction or disappearance of the symptoms of claudicatio intermittens.
- Nicergoline has no emetic effects. Even at high doses. Trials aimed at evaluating the peripheral blood flow demonstrated that Nicergoline is more active than nicotinic acid and lacks the unwanted side effects which are characteristic of that drug.
- doses as high as 10-15 mg or more/day. distributed over a whole day. can be administered by the intramuscular route.
- the intravenous route can be used. especially during the first stage of the treatment or according to the clinical need. Doses ranging between l-3 mg and 10 mg can be administered by slow infusion in 100-250 ml of saline solution (one or more times a day). In special cases. the intra-arterial route was used. which. however. fails to offer the advantages of a prolonged effect.
- EXAMPLE I l-methyl-lumilysergol-8-(5'-bromonicotinate)- l0- methylether also known as 1.6-dimethyl-8-beta-(5- bromonicotinoyl-oxymethyl l O-alpha-m ethoxyergoline.
- EXAMPLE 2 l-Methyl-lumilysergol-S-acetate-lO-methylether Operating as described in Example 1. but employing acetyl chloride as acylating agent. l-methyllumilysergol-8-acetate-lO-methylether was obtained. mctling at ll5l l7C; [01],, 10 (c 0.2 in pyridine).
- EXAMPLE 4 l-Methyl-lumilysergol-8-nicotinatel O-methylether Operating as described in Example I. but employing nicotinoyl as acylating agent. l-methyl-lumilysergol-8- nicotinate-IO-methylether melting at 202203C was obtained: [01],, l2 (c 0.2 in pyridine).
- a method of inhibiting blood platelet aggregation in the treatment of a cerebral and peripheral metabolic vascular disorder selected from the group consisting of cerebral and peripheral arteriosclerosis. Raynaud's disease. vascular cephalagia and migraine. which comprises administering to a human host an amount of the compound l.6-dimethyl-8-B-( 5-bromonicotinoyloxymethyl l O-a-methoxyergoline effective to inhibit blood platelet aggregation.
- a method of inhibiting blood platelet aggregation in the treatment of cerebral thrombosis which comprises administering to a human host an amount of the compound l.6-dimethyl-8-B-( S-bromonicotinoyloxymethyl l O-a-methoxyergoline effective to inhibit blood platelet aggregation.
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Abstract
1,6-DIMETHYL-8 BETA-(5-BROMONICOTINOYL-OXYMETHYL)-10 ALPHAMETHOXY-ERGOLINE, WHICH HAS BEEN GIVEN THE NAME ''''Nicergoline'''' and constitutes a new drug active on cerebral and peripheral metabolic-vascular disorders.
Description
United States Patent 1 Temperilli Apr. 22, 1975 I 1 USE OF 1,6-DIMETHYL-8-B-(5- BROMONICOTINOYLOXYMETHYL)-l0 a-METIIOXYERGOLINE IN TREATING CEREBRAL AND PERIPHERAL METABOLIC VASCULAR DISORDERS [75] Inventor: Aldemio Temperilli. Milan. Italy [73] Assignee: Societa' Farmaceutici Italia S.p.A..
Milan. Italy [22] Filed: Apr. 2, 1973 [21] Appl. No.: 347.342
Related U.S. Application Data [63] Continuation-impart of Scr. N0. ILL-I48. March 15.
1971. abandoned [30] Foreign Application Priority Data Mar. 20 I970 Italy 22184/70 [52] U.S. Cl 424/259; 260/285.5
[5|] Int. Cl A6Iu 27/00 [58] Field of Search 260/285.5; 424/259 [56] References Cited UNITED STATES PATENTS H1966 Bcrnardi ct al. 260/2855 OTHER PUBLICATIONS Arcari et 111.. British 1. of Pharm., Nov. I968, Vol. 34, N0. 3. p. 700.
Primary E.\'aminerStanley J Friedman Almrney. Agenl, 0r Firm-Hubbell, Cohen & Stiefel 2 Claims. No Drawings 1 2 USE OF wherein R is a radical selected from the group consist- 1 5 ing of methyl. phcnyl. pyridyl-(3)-. fi-methyl-pyridvl- (3 and 5-bromop \'ridyl-(3 Compounds of formula lll are described and claimed in US. Pat. No. 3.228.943 and have remarkable phar- BROMONICOTINOYLOXYMETHYL)-l a-METIIOXYERGOLINE IN TREATING CEREBRAL AND PERIPHERAL METABOLIC macological activity as adrenolytic and anti-serotoninic VASCULAR DISORDERS agents. The process described in this patent is:
coo
CH OH LiAlI-I RIO ca on Esterification I R (III) This is a continuation-in-part of application Ser. No. {H 24.448 filed March l5 I971. now abandoned. R H
The present invention has among its objects new pro- R R 'esses for using l-methyI-lumilysergol-lO-methylether $222 hmmg l 4 StCIS 0f the formula: R: is selected from the group consisting of 40 hydrogen and of a radical of:
A) a saturated carhoxylic aliphatic acid having from 1 to 4 carbon atoms: h) diethylcarhamic acid: c) free henzoic acid which may be substituted h a methoxy and h CO R a chlorine atom:
' 4; d) free or substituted nicotinic acid.
Italian Patent Application No. 16762 A/69, filed on May 13. I969 describes a process for the preparation of lumilysergic acid derivatives according to the scheme:
C OOH (III) -I't COOR R-OH/mineral acid in the presence of light wherein R is a lower alkyl having from 1 to 4 carbon atoms.
The process allows one to obtain the important intermediate I from commercial monohydrate lysergic acid. This intermediate l. according to the process of the above-mentioned U.S. Pat. No. 3.228.943. is transformed into the useful end products [1]. According to the above-mentioned U.S. Pat. No. 3.228.943, the methylation step may be performed before or after the irradiation step with U.V. light in order to obtain the useful ergoline end products lll having a methyl group attached to the nitrogen atom in position 1. The methylation step may be carried out by reacting the nonmethylated ergolines in position 1 with methyl iodide in liquid ammonia in the presence of potassium amide.
It has now been found. and it is one of the objects of the present invention. that it is more advantageous to carry out the methylation at the end of the reaction sequence, according to the scheme:
CH O
EsterificationE CH O-CO-R Finally. the lumilysergol-IO-methylether esters thus formed are methylated in position 1 of the ergolinic ring. The above-mentioned methylation is performed in a manner known per se by reacting the esters dissolved in liquid ammonia with methyl iodide in the presence of potassium amide.
The potassium amide is produced in the same reaction solution by dissolving metallic potassium in liquid ammonia and this solution is oxidized by treatment with ferric nitrate. Afterwards. the lumilysergol-IO- methylether ester is added to a liquid ammonia solution which is treated with methyl iodide. The mixture is allowed to react for a period of from 1 to 2 hours and at a temperature of from 60 to 30C. It is preferable, to use a slight excess of potassium amide and methyl iodide.
When the reaction is over, the ammonia is evaporated and the residue is taken up with crushed ice and an organic solvent immiscible with water, such as chlo- CH O-CO -R Methylation ICH liq NH K roform. The desired product is contained in the organic layer. The mixture is evaporated in vacuo to dryness and the residue is recrystallized from a suitable solvent selected from the group consisting of esters and lower aliphatic ketones such as ethyl ether and acetone.
It has also been ascertained that 1.6-dimethyl-8 beta- (5-bromonicotinoyl-oxymethyl l 0 alpha-methoxyergoline. which is called Nicergoline, is a new drug which displays valuable activity on cerebral and peripheral metabolic-vascular disorders. PHARMACOLOGICAL PROPERTIES of Nicergoline Nicergoline antagonizes the effects of exogenous and endogenous eatecholamines on adrenergic receptors because of its alpha-adrenoceptor blocking activity.
The drug possesses a marked myorelaxant action on vessel walls. at the level of musculo-cutaneous vascular districts of the limbs as well as of the exoand endocranial vessels. which causes an increase in the arterial blood flow. Peripheral vasodilatation takes place at doses which do not significantly affect the splanchnic blood flow or the most important cardiovascular parameters (systemic arterial blood pressure. heart rate. cardiac output).
Unlike hydrogenated ergot alkaloids. Nicergoline does not modify the hypertensive effects due to stimu lation of hypothalamic and bulbar centers. Nicergoline clearly differs from the ergot alkaloids in that it does not cause vasoconstriction and does not have any emetic effect. even at high doses.
The drug exerts a specific antagonist action on focal cardiac necroses caused by phenylephrine.
At the brain level. under pathological hypoxic conditions, Nicergoline causes an increase in the uptake of cerebral glucose and of cerebral 0 as well as a stimulation of brain metabolizing activity. It also acts on the energy state of the brain by favoring the conversion of adenylates into higher energy forms.
Cerebral functions are positively influenced by Nicergoline as shown by a faster recovery of EEG patterns and evoked cortical potantials in ischemic brains of cats treated with the drug. Simultaneously with the effect on the restoration of the cerebral function. a restoration of the ATPase activity of nervous cells occurs as has been revealed by biochemical examinations.
In vitro tests carried out in various animal tissues, Nicergoline causes an accumulation of cyclic AMP in the brain only. probably in connection with its stimulating action on adenylcyclase or with its blocking action of phosphodiesterase in this tissue.
Nicergoline affects the cerebral hemodynamics by decreasing vascular resistance and by increasing blood flow. while it does not interfere with the autoregulation of cerebral vessels. The effects of the drug on metabolism and on cerebral flow in animals are further confirmed by both direct and indirect results of studies carried out in man.
Nicergoline causes an increase of muscular activity. as shown by a higher resistance to muscular fatigue in the mouse.
Nicergoline inhibits in vitro. the aggregation of human platelets, induced by various aggregating agents. In animals. the antiaggregating effect is demonstrated in experimental platelet thrombosis, where the drug inhibits the formation of platelet thrombi.
ln man. given at therapeutic doses by oral route. Nicergoline is able to inhibit the induced platelet aggregation.
MECHANISM OF THE ACTION of Nicergoline Nicergoline possesses a selective blocking activity on alpha-adrenergic receptors.
It causes arteriolar vasodilatation both through a vascular mechanism and through modifications of the tissue metabolism. At the level of the brain it acts. under pathological hypoxic conditions or in the case of decreased efficiency, by activating its metabolism, by restoring the energy balance and by bringing hemodynamics toward normal. It exerts an inhibiting effect on platelet aggregation.
PHARMACOKINETICS A comparative examination of the results obtained by Nicergoline in rats. in monkeys and in man with radioactive compounds. indicates that Nicergoline is rapidly absorbed both by the subcutaneous and the oral route with large amounts being found in the liver and in the kidney. While it rapidly disappears from the liver. where it is probably metabolized. high concentrations remain in the kidney which is the main excretory route of the metabolites of the drug. Nicergoline is fully metabolized and most of its metabolites have been identified.
CLINICAL ACTIVITY Studies performed on over 1.000 human patients. including 259 patients checked by means of double blind trials. clearly demonstrated the usefulness of Nicergoline.
In patients suffering from subacute and chronic cerebral vasculopathies. the effects induced by Nicergoline were evaulated with various techniques. and modifications of metabolism and of cerebral hemodynamics toward the normal standard were evidenced.
Both an increase in oxygen and glucose consumption and an increase in the blood flow were observed.
Rheoencephalographic modifications of a rejuvenation" type as well as the normalization of the radiocirculographic curve were reported.
The electroencephalograms (EEG) showing paroxysmal cuspidal anomalies were often rapidly improved.
A distinctive characteristic of Nicergoline is activity at the level of the brain under pathological conditions of a metabolic-vascular origin. where it acts with a multiple mechanism of action. In these cases. the drug causes stimulation of the metabolism of nervous cells and an increase of cerebral blood flow.
The above effects were confirmed by clinical phar' macology trials as well as by pharmacotherapy studies. in which significant improvements in the neurological. psychic and general symptomatology were reported.
More specifically an improvement of motor defects. sensorial disturbances. aphasic and dysarthric symptoms was demonstrated in subacute stroke patients. A clear improvement in the various disorders examined was also observed with regard to subjective symptomatology (cephalalgia. vertigo. ear buzzing. vision troubles. asthenia. insomnia. increased sensitivity to cold). Finally. unquestionably positive results were obtained with regard to the psycho-affective sphere: characteristic symptoms, such as impairment of concentration and thinking. loss of memory. reduced attention. personal ity disorders. disorientation. mental confusion. affective lability, emotivity. agitation, either subsided or totally disappeared. Remarkable prophylactic and therapeutic results were also obtained in the case of vascular cephalalgias and migraine.
Obliterative and functional peripheral arteriopathies of various nature (Burger's disease. arteriosclerosis. diabetes. Raynauds disease) represent another field of clinical employment of Nicergoline. In this field. a clear increase in the peripheral blood flow was evidenced by trials performed with radioisotope clearance. rheography. plethysmography. morpho-oscillography and cutaneous thermometry.
Clinical therapeutic results were represented by an improvement of the muscle-cutaneous blood flow. an improvement of trophic lesions. a decrease in hypersensitivity to cold and the reduction or disappearance of the symptoms of claudicatio intermittens.
Throughout the extensive clinical trials. the drug was perfectly tolerated and proved practical to handle. Unlike other drugs possessing a vasodilating effect. Nicergoline does not cause orthostatic hypotension. at therapeutic doses.
Only in hypertensive patients is there a gradual and slight decrease of blood pressure values. The hypotensive effect of drugs administered simultaneously with Nicergoline can be potentiated.
Unlike dihydroergotoxine. Nicergoline has no emetic effects. even at high doses. Trials aimed at evaluating the peripheral blood flow demonstrated that Nicergoline is more active than nicotinic acid and lacks the unwanted side effects which are characteristic of that drug.
INDICATIONS FOR USE Diffuse cerebral arteriosclerosis Cerebral arteriosclerosis in hypertension Cerebral arteriosclerosis in diabetes Thrombosis and cerebral embolism (stroke) at the subacute stage Transient cerebral ischemia lnvolution syndromes of presenile age. senescence. senility Prophylaxis of vascular cephalalgia and migraine Peripheral vasculopathies of various etiologies (functional vasculopathies. Raynauds disease. arteriosclerosis. diabetes. Burger's disease).
POSOLOGY Doses of -10 mg of Nicergoline" were administered three times a day orally for periods of several months. either for prophylactic or therapeutic purposes. During the first stage of treatment. that is. for a period of about days. and especially for serious.
cases. it is advisable to administer Nicergoline by the intramuscular route. at doses of l-4 mg distributed over a whole day.
In the case of obliterative peripheral arteriopathies.
doses as high as 10-15 mg or more/day. distributed over a whole day. can be administered by the intramuscular route.
The intravenous route can be used. especially during the first stage of the treatment or according to the clinical need. Doses ranging between l-3 mg and 10 mg can be administered by slow infusion in 100-250 ml of saline solution (one or more times a day). In special cases. the intra-arterial route was used. which. however. fails to offer the advantages of a prolonged effect.
The following examples are to illustrate the present invention without limiting it.
EXAMPLE I l-methyl-lumilysergol-8-(5'-bromonicotinate)- l0- methylether also known as 1.6-dimethyl-8-beta-(5- bromonicotinoyl-oxymethyl l O-alpha-m ethoxyergoline.
1.40 g of S-bromo-nicotinoyl chloride were added.
with stirring to a solution of 0.4 g of lumilysergol-lO- mcthylether (prepared according to Example 8 of the U5. Pat. No. 3.228.943) in 68 ml of pyridine cooled to 0C. The mixture was allowed to stand for 3 hours with stirring. It was then evaporated in vacuo to dryness. taken up with crushed ice and the pH was adjusted to ll with sodium hydroxide and extracted with chloroform. The chloroform extract was washed with water and evaporated in vacuo to dryness. The residue was recrystallized from ethyl ether. 2 g of lumilysergol-IO- mcthylether 5 -bromonicotinate melting at l95-l96C were obtained. 0.242 g of potassium metal was dissolved in 50 ml ofliquid ammonia and 0.020 gof ferric nitrate were added to catalyze the formation of potassium amide. Later 2 g of lumilysergol-lO-methylether 5'-bromonicotinate. obtained as above-mentioned. were added and after 15 minutes 0.88 g of methyl iodide. After 15 minutes 0.4 g of ammonium chloride was added. The ammonia was evaporated in a nitrogen atmosphere at room temperature. the residue was taken up with crushed ice and chloroform. The chloroform layer. in which the desired product is dissolved, was separated. and then evaporated to dryness. The residue was recrystallized from ethyl ether. l-methyllumilysergol-8-( 5 '-bromo-nicotinate l O-methylether. also known as l.6-dimethyl-8 beta-( 5- bromonicotinoyl-oxymethyl)-l0-alpha-methoxyergoline. was thus obtained. melting at l38l39C; [01],, 20 (c l in pyridine).
EXAMPLE 2 l-Methyl-lumilysergol-S-acetate-lO-methylether Operating as described in Example 1. but employing acetyl chloride as acylating agent. l-methyllumilysergol-8-acetate-lO-methylether was obtained. mctling at ll5l l7C; [01],, 10 (c 0.2 in pyridine).
EXAMPLE 3 l-Methyl-lumilysergol-8-benzoatel O-methylether Operating as described in Example 1. but employing benzoyl chloride as acylating agent. l-methyllumilysergol-8-benzoate-lO-methylether was obtained. melting at l67l69C; [ctl 40 (0 0.3 in pyridine).
EXAMPLE 4 l-Methyl-lumilysergol-8-nicotinatel O-methylether Operating as described in Example I. but employing nicotinoyl as acylating agent. l-methyl-lumilysergol-8- nicotinate-IO-methylether melting at 202203C was obtained: [01],, l2 (c 0.2 in pyridine).
EXAMPLE 5 l-Methyl-lumilysergol-8-( 6 '-methylnicotinate I 0- mcthylether Operating as described in Example I. but employing o-methyl-nicotinoyl as acylating agent. l-methyllumilysergol-8-( 6-methylnicotinate l O-methylether melting at l44-l46C was obtained.
[ claim:
1. A method of inhibiting blood platelet aggregation in the treatment of a cerebral and peripheral metabolic vascular disorder selected from the group consisting of cerebral and peripheral arteriosclerosis. Raynaud's disease. vascular cephalagia and migraine. which comprises administering to a human host an amount of the compound l.6-dimethyl-8-B-( 5-bromonicotinoyloxymethyl l O-a-methoxyergoline effective to inhibit blood platelet aggregation.
2. A method of inhibiting blood platelet aggregation in the treatment of cerebral thrombosis. which comprises administering to a human host an amount of the compound l.6-dimethyl-8-B-( S-bromonicotinoyloxymethyl l O-a-methoxyergoline effective to inhibit blood platelet aggregation.
mg? UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N 0. 3,879,554 D d April 22, 1975 lnventofls ALDEMIO TEMPERILLI It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
Title page, leftside, under "Foreign Application Priority Data": "22184/70" should read 22l84-A/7O Title page, right side, under "Abstrate" line 3:
"'Nicergoline' and constitutes" should read "Nicergoline", constitutes Column 1, line 36: "24,448" should read 124,448
Column 1, lines 37-38: "proesses" should read processes Column 1, line 39: "stars" should read esters Column 2, line 40: "A) should read a) Column 5, line 26: "potantials" should read potentials Column 5, line 31: "In vitro" should read In in vitro Column 6, line 16: "evaulated" should read evaluated Column 8, line 1: "were" should read was Signed and sealed this lst day of July 1975.
SEAL) Attest:
T C MARSHALL DANN RULI; C AQOE. Commissioner of Patents Attesting OfflCel" and Trademarks
Claims (2)
1. A METHOD OF INHABITING BLOOD PLATELET AGGREGATION IN THE TREATMENT OF A CEREBRAL AND PERIPHERAL METABOLIC VASCULAR DISORDER SELECTED FROM THE GROUP CONSISTING OF CEREBRAL AND PERIPHERAL ARTERIOSCLEROSIS, RAYNAUD''S DISEASE, VASCULAR CEPHALAGIA AND MIGRANIE, WHICH COMPRISES ADMINISTERING TO A HUMAN HOST AN AMOUNT OF THE COMPOUND 1,6-DIMETHYL-8-B-(5BROMO-NICOTINOYLOXYMETHYL)-10-A-METHOXYERGOLINE EFFECTIVE TO INHABIT BLOOD PLATELET AGGREGATION.
1. A method of inhibiting blood platelet aggregation in the treatment of a cerebral and peripheral metabolic vascular disorder selected from the group consisting of cerebral and peripheral arteriosclerosis, Raynaud''s disease, vascular cephalagia and migraine, which comprises administering to a human host an amount of the compound 1,6-dimethyl-8- Beta -(5-bromo-nicotinoyloxymethyl)-10- Alpha -methoxyergoline effective to inhibit blood platelet aggregation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US347342A US3879554A (en) | 1970-03-20 | 1973-04-02 | Use of 1,6-dimethyl-8-{62 -(5-bromonicotinoyloxymethyl)-10 {60 -methoxyergoline in treating cerebral and peripheral metabolic vascular disorders |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2218470 | 1970-03-20 | ||
| US12444871A | 1971-03-15 | 1971-03-15 | |
| US347342A US3879554A (en) | 1970-03-20 | 1973-04-02 | Use of 1,6-dimethyl-8-{62 -(5-bromonicotinoyloxymethyl)-10 {60 -methoxyergoline in treating cerebral and peripheral metabolic vascular disorders |
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| US3879554A true US3879554A (en) | 1975-04-22 |
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| US347342A Expired - Lifetime US3879554A (en) | 1970-03-20 | 1973-04-02 | Use of 1,6-dimethyl-8-{62 -(5-bromonicotinoyloxymethyl)-10 {60 -methoxyergoline in treating cerebral and peripheral metabolic vascular disorders |
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Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3929796A (en) * | 1974-08-02 | 1975-12-30 | Lilly Co Eli | Synthesis of penniclavine and elymoclavine |
| US3968112A (en) * | 1974-08-02 | 1976-07-06 | Eli Lilly And Company | Synthesis of penniclavine and elymoclavine |
| US4082753A (en) * | 1976-02-17 | 1978-04-04 | Eli Lilly And Company | Penniclavine acetonide |
| US4230859A (en) * | 1977-07-21 | 1980-10-28 | Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, N.Sol.O. | Process for the preparation of N-substituted esters of 9,10-dihydrolysergicacids |
| US4232157A (en) * | 1978-04-05 | 1980-11-04 | Corvi Mora E | Process for preparing lysergol derivatives |
| EP0122044A1 (en) * | 1983-03-10 | 1984-10-17 | Eli Lilly And Company | Selective method for blocking 5HT2 receptors |
| US4739061A (en) * | 1985-07-11 | 1988-04-19 | Rhone-Poulenc Sante | Process for preparing n-methyl derivatives of methyl dihydrolysergate and methyl methoxylumilysergate |
| US4754037A (en) * | 1985-07-11 | 1988-06-28 | Rhone-Poulenc Sante | Process for preparing N-methyl derivatives of ergoline |
| US4753949A (en) * | 1985-06-21 | 1988-06-28 | Richter Gedeon Vegyeszeti Gyar Rt. | 2-chloronicergoline having antihypoxic activity |
| US4785001A (en) * | 1986-05-21 | 1988-11-15 | Farmitalia Carlo Erba S.P.A. | Ergoline esters |
| US4843073A (en) * | 1986-06-25 | 1989-06-27 | Farmitalia Carlo Erba S.P.A. | 1-t-butyl ergolines useful in the treatment of cerebral insufficiency and senile dementia |
| US4870179A (en) * | 1984-08-07 | 1989-09-26 | Inverni Della Beffa Spa | Process for preparing lysergol derivatives |
| US4908449A (en) * | 1985-07-11 | 1990-03-13 | Rhone-Poulenc Sante | Process for preparing N-methyl derivatives of lysergol and 10α-methoxylumilysergol |
| US4980475A (en) * | 1984-03-27 | 1990-12-25 | I D B Holding S.P.A. | Process for the preparation of N-10 alpha-methoxyl-lumilysergol and esters, thereof, and intermediates for their preparation |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3228943A (en) * | 1962-06-11 | 1966-01-11 | Lumilysergol derivatives |
-
1973
- 1973-04-02 US US347342A patent/US3879554A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3228943A (en) * | 1962-06-11 | 1966-01-11 | Lumilysergol derivatives |
Cited By (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3968112A (en) * | 1974-08-02 | 1976-07-06 | Eli Lilly And Company | Synthesis of penniclavine and elymoclavine |
| US3929796A (en) * | 1974-08-02 | 1975-12-30 | Lilly Co Eli | Synthesis of penniclavine and elymoclavine |
| US4082753A (en) * | 1976-02-17 | 1978-04-04 | Eli Lilly And Company | Penniclavine acetonide |
| US4230859A (en) * | 1977-07-21 | 1980-10-28 | Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, N.Sol.O. | Process for the preparation of N-substituted esters of 9,10-dihydrolysergicacids |
| US4232157A (en) * | 1978-04-05 | 1980-11-04 | Corvi Mora E | Process for preparing lysergol derivatives |
| EP0122044A1 (en) * | 1983-03-10 | 1984-10-17 | Eli Lilly And Company | Selective method for blocking 5HT2 receptors |
| US4980475A (en) * | 1984-03-27 | 1990-12-25 | I D B Holding S.P.A. | Process for the preparation of N-10 alpha-methoxyl-lumilysergol and esters, thereof, and intermediates for their preparation |
| US4870179A (en) * | 1984-08-07 | 1989-09-26 | Inverni Della Beffa Spa | Process for preparing lysergol derivatives |
| US4753949A (en) * | 1985-06-21 | 1988-06-28 | Richter Gedeon Vegyeszeti Gyar Rt. | 2-chloronicergoline having antihypoxic activity |
| US4908449A (en) * | 1985-07-11 | 1990-03-13 | Rhone-Poulenc Sante | Process for preparing N-methyl derivatives of lysergol and 10α-methoxylumilysergol |
| US4754037A (en) * | 1985-07-11 | 1988-06-28 | Rhone-Poulenc Sante | Process for preparing N-methyl derivatives of ergoline |
| US4739061A (en) * | 1985-07-11 | 1988-04-19 | Rhone-Poulenc Sante | Process for preparing n-methyl derivatives of methyl dihydrolysergate and methyl methoxylumilysergate |
| US4785001A (en) * | 1986-05-21 | 1988-11-15 | Farmitalia Carlo Erba S.P.A. | Ergoline esters |
| US4843073A (en) * | 1986-06-25 | 1989-06-27 | Farmitalia Carlo Erba S.P.A. | 1-t-butyl ergolines useful in the treatment of cerebral insufficiency and senile dementia |
| WO1993019271A1 (en) * | 1992-03-26 | 1993-09-30 | Sako Oga | Parking space barrier |
| US7923467B2 (en) | 2003-05-30 | 2011-04-12 | Ranbaxy Laboratories, Inc. | Substituted pyrrole derivatives and their use as HMG-CO inhibitors |
| US20100056602A1 (en) * | 2003-05-30 | 2010-03-04 | Ranbaxy Laboratories Limited | Substituted Pyrrole Derivatives And Their Use As HMG-CO Inhibitors |
| US20110190296A1 (en) * | 2003-05-30 | 2011-08-04 | Ranbaxy Laboratories Limited | Substituted Pyrrole Derivatives and Their Use as HMG-CO Inhibitors |
| US20110190369A1 (en) * | 2003-05-30 | 2011-08-04 | Ranbaxy Laboratories Limited | Substituted Pyrrole Derivatives and Their Use as HMG-CO Inhibitors |
| US20080248035A1 (en) * | 2005-11-08 | 2008-10-09 | Ranbaxy Laboratories | Pharmaceutical Combination |
| US20080287690A1 (en) * | 2005-11-08 | 2008-11-20 | Ranbaxy Laboratories Limited | Process For (3R, 5R)-7-[2-(4-Fluorophenyl)-5-Isopropyl-3-Phenyl-4- [(4-Hydroxy Methyl Phenyl Amino) Carbonyl]-Pyrrol-1-Yl]-3,5-Dihydroxy-Heptanoic Acid Hemi Calcium Salt |
| US20090118520A1 (en) * | 2005-11-08 | 2009-05-07 | Ranbaxy Laboratories Limited | Process for preparation of (3r, 5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt |
| US7671216B2 (en) | 2005-11-08 | 2010-03-02 | Ranbaxy Laboratories Limited | Process for preparation of (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt |
| US7956198B2 (en) | 2005-11-08 | 2011-06-07 | Ranbaxy Laboratories, Limited | Pharmaceutical compositions |
| US8026377B2 (en) | 2005-11-08 | 2011-09-27 | Ranbaxy Laboratories, Limited | Process for (3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid hemi calcium salt |
| US20070238716A1 (en) * | 2006-03-14 | 2007-10-11 | Murthy Ayanampudi S R | Statin stabilizing dosage formulations |
| US20080153896A1 (en) * | 2006-07-14 | 2008-06-26 | Gyan Chand Yadav | Polymorphic Forms of an HMG-CoA Reductase Inhibitor and Uses Thereof |
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Owner name: FARMITALIA CARLO ERBA S.P.A., Free format text: MERGER;ASSIGNORS:CARLO ERBA S.P.A.;SOCIETA FARMACEUTICI ITALIA S.P.A., KNOWN AS FARMITALIA S.P.A.;REEL/FRAME:003981/0134 Effective date: 19801007 |
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