GB1590149A - Ergot alkaloid peptide derivatives - Google Patents
Ergot alkaloid peptide derivatives Download PDFInfo
- Publication number
- GB1590149A GB1590149A GB36338/77A GB3633877A GB1590149A GB 1590149 A GB1590149 A GB 1590149A GB 36338/77 A GB36338/77 A GB 36338/77A GB 3633877 A GB3633877 A GB 3633877A GB 1590149 A GB1590149 A GB 1590149A
- Authority
- GB
- United Kingdom
- Prior art keywords
- compound
- desoxo
- formula
- compounds
- dihydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/02—Ergot alkaloids of the cyclic peptide type
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Cardiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
(54) ERGOT ALKALOID PEPTIDE DERIVATIVES
(71) We, SANDOS LTD., of 35 Lichtstrasse, 4002 Basle, Switzerland, a
Swiss Body Corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in an by the following statement:- The present invention relates to ergot peptide alkaloid derivatives.
The present invention provides compounds of formula I,
wherein
R1 is alkyl of 1 to 4 carbon atoms,
R2 is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl,
R3 and Rs are, independently, hydrogen or methyl,
R4 is hydrogen or alkyl of 1 to 4 carbon atoms, and
R6 and R7 together form a single bond, or
R6 and R7 are each hydrogen, or
R6 is methoxy and R7 is hydrogen.
A group of compounds comprises compounds of formula I with the proviso that when R4 is methyl the compound of formula I is
(a) 6'-desoxo-9, 10-dihydroergocornine;
(b) 6'-desoxo-9,10-dihydro-p-ergosine;
(c) 6'-desoxo-ergotamine;
(d) 6'-desoxo-ergocrystine;
(e) 6'-desoxo-pergocryptine or
(f) 6'-desoxo-a-ergocryptine.
In formula I, R, is for example methyl, ethyl or isopropyl. R2 is conveniently nor iso-propyl, n, iso- or sec.-butyl or benzyl. R3 and R5 conveniently are both hydrogen. R4 is conveniently methyl or iso-propyl. R6 and R7 are preferably each hydrogen.
The present invention also provides a process for the production of a compound of formula I, which comprises a) reducing the 6' carbonyl group in a compound of formula II,
wherein
R1 to R7 are as defined above, or
b) condensing an acid addition salt of a compound of formula III,
wherein
R, to R3 are as defined above, with a reactive acid derivative of a compound of formula IV,
wherein
R4 to R7 are as defined above.
Process a) may be effected in one step if desired, using reactive borane, e.g.
diborane. The process may be effected in conventional manner for diborane reductions under mild conditions. Conveniently 5 to 15 moles of reactive borane are used per mole of a compound of formula II. Tetrahydrofuran, diethyl ether or methylene chloride may be used as solvent. Suitable reaction temperatures may be from 200 to 20"C.
Process b) may be effected in conventional manner for condensations to produce analogous ergot cyclic peptide alkaloids.
A suitable acid addition salt of a compound of formula III is the 2,5naphthalene-disulphonic acid salt.
Suitable reactive acid derivatives of a compound of formula IV include the acid chloride, the acid azide, and the mixed anhydride with sulphuric or trifluoroacetic acid. It is preferred to use the reactive acid derivative of a compound of formula IV arising out of the reaction of a compound of formula IV with dimethyl formamide or acetamide and thionyl chloride, phosgene or oxalyl chloride. Preferably triethylamine or pyridine is present during the reaction.
Suitable solvents include chloroform, methylene chloride, dimethyl formamide and acetonitrile.
Suitable reaction temperatures are from 300 to +200C.
The starting materials are known or may be produced in conventional manner from known compounds. Thus a compound of formula III may be prepared in known manner for the preparation of an aminocyclol from a compound of formula
V:
wherein
R1 to R3 are as defined above.
For example the corresponding acid may first be formed and then converted via the acid chloride into the corresponding acid amide, which in turn is converted into the amine.
A compound of formula V may be produced by reacting a compound of formula VI,
wherein
R1 is as defined above, with a compound of formula VII,
wherein
R2 and R3 are as defined above, and hydrogenating the resultant product.
A compound of formula VII may be produced by reducing a compound of formula VIII,
wherein
R2 and R3 are as defined above, with lithium aluminium hydride.
Free base forms of the compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids for salt formation include hydrochloric and methane-sulphonic acids.
In the following Examples all temperatures are in degrees Centigrade and are uncorrected.
The title compounds of Examples 1 and 2 form no part of the present invention. They illustrate, however, the processes of the invention and the preparation of the starting materials. The title compound of Example 1 is claimed in our divisional application No. 8009862 (Serial No. 1,590,150).
EXAMPLE 1 6'-desoxo-9, 1 0-dihydro-p-ergocryptine [process a)1 1.15 g of 9,10-dihydro-p-ergocryptine (2 mmols) are suspended and stirred at 0 in 25 ml of absolute tetrahydrofuran and then a freshly prepared solution of 20 mmoles reactive borane (e.g. NaBH4 and boron trifluoride etherate) in 35 ml of absolute tetrahydrofuran is added dropwise. After stirring for 4 hours at 00 the solution is cooled. The reaction mixture is carefully treated with 9 ml of 6Nhydrochloic acid, and then stirred for another 30 minutes at +60 , cooled, made alkaline with 30% sodium hydroxide, and then thoroughly extracted with methylene chloride. The methylene chloride extracts are chromatographed on alumina (activity II--III) to yield the title compound in free base form which is recrystallized from methylene chloride/ether. M.Pt. 159160 ; [a] 2D040 (c=0. 5 DMF).
The title compound may also be prepared according to the process of Example 2.
EXAMPLE 2 1-methyl-6'-desoxo-9, 10-dihydroergocristine [process b)]
A solution of 1.14 ml (17.14 mmole) of oxalyl chloride in 15 ml of absolute acetonitrile is added dropwise to 150 ml of absolute dimethyl formamide at 150.
4.87 g (17.14 mmols) of dry l-methyl-9,10-dihydrolysergic acid are then added, and a grey deposit precipitates from the reaction mixture. After stirring for 30 minutes at 0 , the mixture is cooled and treated with 37.5 ml of absolute pyridine, and then 5.14 g of (2R,5S,l0aS,l0bS) - 2 - amino - 2 - isopropyl - 3 - oxo - 5 - benzyl
lOb - hydroxy - perhydrooxazolo[3,2 - a] - pyrrolo[2,1 - c]pyrazine.2,5 naphthalene - disulphonic acid (about 8.5 mmols) are added. The mixture is stirred vigorously for 2 hours, and then the temperature is allowed to increase slowly from -10" to 00. The mixture is then cooled again and diluted with 40 ml of citrate
buffer (pH=4), and then made alkaline with 2N soda solution. After extraction with chloroform containing a small amount of ethanol, the extract is dried and evaporated. The crude product is chromatographed on silicagel, to give the title compound in free base form on elution with 4% methanol in methylene chloride, which is recrystallised from acetone. M.Pt. 183"--185"; [al2DO=770 (c=l, pyridine).
The title compound may also be prepared by the process of Example 1.
The 2 - amino - 2 - isopropyl - 3 - oxo - 5 - benzyl - lOb - hydroxy perhydrooxazolo[3,2 - a]pyrrolo[2,1 - c]pyrazine.2,5 - naphthalene - disulphonic acid is obtained as follows:- a) (2S,7aS)-2-benzylperhydro-8-oxo-pyrrolo[2,I-c]pyrazine 36.4 g (960 mmols) of lithium aluminium hydride are suspended in 1.3 litres of absolute tetrahydrofuran in a nitrogen atmosphere, and a solution of 117.2 g (480 mmols) of L-Phe-L-Pro-lactam in 1.4 litres of absolute tetrahydrofuran is added dropwise over 45 minutes. After stirring for 18 hours at 100, the reaction mixture is diluted carefully at this temperature with 350 ml of ethyl acetate and then 350 ml of water. The resultant mixture is filtered. Repeated extraction of the filter cake with boiling methylene chloride is effected to obtain more product. The combined organic phases and filtrate are dried with sodium sulphate and evaporated. The pure title compound in free base form crystallises directly from methylene chloride/ether in bright beige crystals; M.Pt. of 135 140 ; [α]D20=-3.5 (c=l in ethanol).
b) (2R,5S, 10aS, 1 ObS)-2-carbethoxy-2-isopropyl-3-oxo- 5-benzyl- 1 Ob-hydroxy perhydro-oxazolo[3,2-aipyrrolo [2,1 -cipyrazine b)i) 47.8 g (207 mmols) of (2S,7aS)-2-benzyl-perhydro-8-oxo-pyrrolo[2,1- c]pyrazine in 160 ml of absolute dioxane are treated with 74.4 g (249 mmols) of S (+)-isopropyl-benzyloxy-malonic acid mono-ethyl ester mono-acid chloride and 34.9 g (270 mmols) of N-ethyldiisopropylamine. The mixture is stirred for 1 hour at +700. After dilution with 1 litre of ether, the mixture is shaken twice with saturated sodium bicarbonate solution and dried over sodium sulphate. After evaporation of the solvent, 138 g of a brownish oil containing (2S,7aS) - (2'S - 2' - benzyloxy 2' - isopropyl - O - ethylmalononyl)- 2 - benzyl - perhydro - 8 - oxo pyrrolo[2,l - c]pyrazine are obtained.
b)ii) This oil is dissolved in 1.5 litres of ethanol and is hydrogenated at 600 after addition of 60 g of palladium-active carbon (100/, w/w Pd), wherein, after 14 hours, about 6.5 litres of hydrogen are absorbed. After filtration and evaporation of the filtrate, the title compound is recrystallized from isopropyl ether, as yellowish prisms with a M.Pt. of 99 100 ; [a]20=57.70 (c=0.65 in CHCI3).
c) (2R,5S, lOaS, 10bS)-2-carboxy-2-isopropyl-3-oxo-5-benzyl- 1 Ob-hydroxy- perhydro-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine
39.3 g (97.8 mmols) of (2R,5S,l0aS,10bS) - 2 - carbethoxy - 2 - isopropyl 3 - oxo - 5 - benzyl - lOb - hydroxy - perhydro - oxazolo[3,2 - a]pyrrolo[2,1 c]pyrazine are dissolved in 245 ml of methanol and 245 ml of 2N sodium hydroxide.
The mixture is stirred for 3 hours at room temperature, adjusted at 0 to a pH of 4.5 with 2N hydrochloric acid, and then extracted repeatedly with ethyl acetate. After drying the organic extract and evaporating the solvent at below +30 , the title compound crystallises after dilution with ether. M.Pt. 126 128 (decomp). After drying for 5 hours at 300 in a high vacuum, the crystals contain 1/2 mol water per mole of title compound.
d) (2R,5S, 10aS, 10bS)-2-amino-2-isopropyl-3-oxo-5-benzyl-10b-hydroxy perhydro-oxazolo[3,2-alpyrrolo[2,1-c]pyrazine.2,5-naphthalene disulphonic acid
di) A solution of 3.84 ml (45 mmols) of oxalyl chloride in 15 ml of absolute acetonitrile is added in drops over 10 minutes to a stirred mixture of 4.33 ml (56.3 mmols) of absolute dimethyl formamide and 30 ml of absolute acetonitrile which is
cooled to -15 . The mixture is stirred for a further 10 minutes. After dilution of the mixture with 45 ml of absolute ether, 11.25 g (30 mmols) of(2R,5S,10aS,I0bS) - 2 carboxy - 2 - isopropyl - 3 - oxo - 5 - benzyl - lOb - hydroxy - perhydro oxazolo[3,2 - a]pyrrolo[2,1 - c]pyrazine.l/2 H20 are quickly added. A clear solution is produced, which is stirred for another 10 minutes at 100 thereby producing the acid chloride.
dii) A solution of 20 g of sodium azide in 100 ml of water, diluted with 300 ml of methylene chloride, is added to the acid chloride solution and the 2-phase mixture is shaken vigorously for 4 minutes. Then, 150 ml of ice-cold, saturated sodium bicarbonate solution are added. The organic phase is separated and dried well over sodium sulphate. After evaporation of the solvent at below 30 , a solution of 7.78 g (27 mmols) of 2,5-naphthalene disulphonic acid in 200 ml of dimethoxyethane and 20 ml of acetonitrile is added. The mixture is then slowly concentrated in a vacuum.
After dilution of the mixture with absolute ether, the acid azide is isolated as the 2,5-naphthalene disulphonate salt.
diii) 6.35 g (~9 mmols) of the salt are heated for 1 hour to 800 in the presence of
120 ml of dimethoxyethane which contains 0.166 ml of water. The title compound is obtained with constant scraping, as a brownish, semi-crystalline powder, which may be used directly after cooling, filtering and drying at room temperature in a high vacuum.
The following compounds may be obtained in analogous manner to that described in Example 1 or 2.
EXAMPLE 3
6'-desoxo-9,10-dihydroergocornine
M.Pt. 166 167 (decomp); [α]D20=18.5 (c=0.66 in dimethylformamide).
EXAMPLE 4
6'-desoxo-9,10-dihydro-p-ergosine
M.Pt. 194 -196 (sintering from 1.850); [a]2g=-18 (c=0.3 in dimethyl formamide).
EXAMPLE 5
6-nor-6-isopropyl-6'-desoxo-9,10-dihydro-ergotamine
M.Pt. 186 -190 ; [a12O=630 (c=0.3 in dimethyl formamide).
EXAMPLE 6
6'-desoxo-ergotamine
M.Pt. 176 180 ; [a]2g=+17 (c=0.35 in dimethyl formamide).
EXAMPLE 7
6'-desoxo-ergocristine
EXAMPLE 8 6'-desoxo-A-ergocryptine EXAMPLE 9 6'-desoxo-a-ergocryptine The compounds of formula I exhibit pharmacological activity. In particular, the compounds of formula I exhibit coronary therapeutic activity as indicated by a coronary dilation and vasodilation in the "open chest cat" test at an effective dose of from about 0.03 to about I mg/kg i.v.
The compounds are therefore indicated for use as coronary therapeutic agents, e.g. for the treatment of angina pectoris.
The compounds also exhibit anti-hypertensive activity as indicated by a blood pressure lowering in the above-mentioned open chest cat test.
The compounds are therefore indicated for use as anti-hypertensives.
An indicated daily dose is from about 10 to about 300 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 2 mg to about 150 mg or in sustained release form.
The compounds may be administered in pharmaceutically acceptable acid addition salt form. Such salt forms have the same order of activity as the free base forms. The present invention provides a pharmaceutical composition comprising a compound of formula I as defined above in association with a pharmaceutical carrier or diluent. Such composition may be formulated in conventional manner so as to be for example a solution or a tablet.
In the following claims we make no claim to the following compounds and methods for their production: 6'-desoxo-9, I 0-dihydroergotamine; 6'-desoxo-9,10- dihydro- I -methylergotamine; 6'-desoxo-9, 1 0-dihydroergocristine; 6'-desoxo-9,10- dihydro-l-methylergocristine; 6'-desoxo-9,10-dihydro-a-ergocryptine and 6' desoxo-9,10-dihydro-p-ergocryptine.
Subject to the foregoing disclaimer,
WHAT WE CLAIM IS:
1. A process for the production of a compound of formula 1,
wherein
R1 is alkyl of 1 to 4 carbon atoms,
R2 is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl,
R3 and R5 are, independently, hydrogen or methyl,
R4 is hydrogen or alkyl of I to 4 carbon atoms, and
R6 and R7 together form a single bond, or
R6 and R7 are each hydrogen, or
R6 is methoxy, and
R7 is hydrogen, which comprises
a) reducing the 6' carbonyl group in a compound of formula II,
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (15)
1. A process for the production of a compound of formula 1,
wherein
R1 is alkyl of 1 to 4 carbon atoms,
R2 is hydrogen, alkyl of 1 to 4 carbon atoms or benzyl,
R3 and R5 are, independently, hydrogen or methyl,
R4 is hydrogen or alkyl of I to 4 carbon atoms, and
R6 and R7 together form a single bond, or
R6 and R7 are each hydrogen, or
R6 is methoxy, and
R7 is hydrogen, which comprises
a) reducing the 6' carbonyl group in a compound of formula II,
wherein
R1 to R7 are as defined above, or
b) condensing an acid addition salt of a compound of formula III,
wherein
R1 to R3 are as defined above, with a reactive acid derivative of a compound of formula IV,
wherein
R4 to R7 are as defined above.
2. A process for the production of a compound of formula I, as stated in Claim
1, substantially as hereinbefore described with reference to any one of the
Examples 1 to 10.
3. A compound of formula I, whenever produced by a process according to
Claim 1 or 2.
4. A compound of formula I, as defined in Claim 1.
5. A compound of Claim 4, which is 6'-desoxo-9, lO-dihydroergocornine.
6. A compound of Claim 4, which is 6'-desoxo-9, l0-dihydro-p-ergosine.
7. A compound of Claim 4, which is 6-nor-6-iso-propyl-6'-desoxo-9,10dihydroergotamine.
8. A compound of Claim 4, which is 6'-desoxo-ergotamine.
9. A compound of Claim 4, which is 6'-desoxo-ergocristine.
10. A compound of Claim 4, which is 6'-desoxo-ss-ergocryptine.
11. A compound of Claim 4, which is 6'-desoxo-a-ergocryptine.
12. A compound of Claim 4 with the proviso that when R4 is methyl the compound is chosen from
(a) 6'-desoxo-9,10-dihydroergocornine,
(b) 6'-desoxo-9,10-dihydro-p-ergosine,
(c) 6'-desoxo-ergotamine,
(d) 6'-desoxo-ergocristine,
(e) 6'-desoxo-,B-ergocryptine, or
(f) 6'-desoxo-a-ergocryptine.
13. A compound of any one of Claims 3 to 12 in free base form.
14. A compound of any one of the Claims 3 to 12 in acid addition salt form.
15. A pharmaceutical composition comprising a compound of any one of
Claims 3 to 12 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1128676A CH623591A5 (en) | 1976-09-06 | 1976-09-06 | Process for the preparation of ergopeptide alkaloid derivatives |
| CH1128776A CH623592A5 (en) | 1976-09-06 | 1976-09-06 | Process for the preparation of ergopeptide alkaloid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1590149A true GB1590149A (en) | 1981-05-28 |
Family
ID=25708069
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB36338/77A Expired GB1590149A (en) | 1976-09-06 | 1977-08-31 | Ergot alkaloid peptide derivatives |
| GB9862/80A Expired GB1590150A (en) | 1976-09-06 | 1977-08-31 | Ergot peptide alkaloid derivative |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9862/80A Expired GB1590150A (en) | 1976-09-06 | 1977-08-31 | Ergot peptide alkaloid derivative |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS5331698A (en) |
| AU (1) | AU512027B2 (en) |
| CA (1) | CA1105007A (en) |
| DE (1) | DE2738730A1 (en) |
| DK (1) | DK147390C (en) |
| ES (1) | ES462080A1 (en) |
| FI (1) | FI64942C (en) |
| FR (1) | FR2363571A1 (en) |
| GB (2) | GB1590149A (en) |
| IE (1) | IE46152B1 (en) |
| IL (1) | IL52896A (en) |
| NL (1) | NL7709683A (en) |
| NZ (1) | NZ185098A (en) |
| PT (1) | PT67003B (en) |
| SE (1) | SE435839B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR112013033339A2 (en) * | 2011-06-23 | 2016-08-16 | Map Pharmaceuticals Inc | fluorergoline analogs |
-
1977
- 1977-06-02 ES ES462080A patent/ES462080A1/en not_active Expired
- 1977-08-27 DE DE19772738730 patent/DE2738730A1/en not_active Withdrawn
- 1977-08-29 DK DK382777A patent/DK147390C/en active
- 1977-08-29 FI FI772557A patent/FI64942C/en not_active IP Right Cessation
- 1977-08-29 SE SE7709645A patent/SE435839B/en unknown
- 1977-08-31 GB GB36338/77A patent/GB1590149A/en not_active Expired
- 1977-08-31 GB GB9862/80A patent/GB1590150A/en not_active Expired
- 1977-09-02 CA CA286,056A patent/CA1105007A/en not_active Expired
- 1977-09-02 NL NL7709683A patent/NL7709683A/en not_active Application Discontinuation
- 1977-09-05 JP JP10596277A patent/JPS5331698A/en active Pending
- 1977-09-05 PT PT67003A patent/PT67003B/en unknown
- 1977-09-05 NZ NZ185098A patent/NZ185098A/en unknown
- 1977-09-05 FR FR7726893A patent/FR2363571A1/en active Granted
- 1977-09-05 IE IE1838/77A patent/IE46152B1/en unknown
- 1977-09-05 IL IL52896A patent/IL52896A/en unknown
- 1977-09-06 AU AU28572/77A patent/AU512027B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IE46152L (en) | 1978-03-06 |
| IL52896A0 (en) | 1977-11-30 |
| PT67003B (en) | 1979-05-14 |
| AU512027B2 (en) | 1980-09-18 |
| DK147390B (en) | 1984-07-16 |
| JPS5331698A (en) | 1978-03-25 |
| DK147390C (en) | 1985-02-04 |
| FR2363571B1 (en) | 1980-04-18 |
| PT67003A (en) | 1977-10-01 |
| AU2857277A (en) | 1979-03-15 |
| IE46152B1 (en) | 1983-03-09 |
| ES462080A1 (en) | 1978-12-01 |
| CA1105007A (en) | 1981-07-14 |
| FI64942B (en) | 1983-10-31 |
| NL7709683A (en) | 1978-03-08 |
| FI64942C (en) | 1984-02-10 |
| GB1590150A (en) | 1981-05-28 |
| SE7709645L (en) | 1978-03-07 |
| FI772557A (en) | 1978-03-07 |
| DK382777A (en) | 1978-03-07 |
| DE2738730A1 (en) | 1978-03-16 |
| FR2363571A1 (en) | 1978-03-31 |
| IL52896A (en) | 1980-07-31 |
| NZ185098A (en) | 1980-04-28 |
| SE435839B (en) | 1984-10-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4401822A (en) | Derivatives of 4-amino-5-alkyl sulphonyl orthoanisamides | |
| JPS60358B2 (en) | Method for producing benzomorphan compounds | |
| PT87988B (en) | PROCESS FOR THE PREPARATION OF DIAZOIS AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM | |
| US5340817A (en) | Method of treating tumors with anti-tumor effective camptothecin compounds | |
| US3586683A (en) | 2,5(5) - di(tri)substituted - 10b-hydroxy-3,6 - dioxo-octahydro-oxazolo(3,2-a) pyrrolo(2,1-c)pyrazine derivatives of lysergic acid | |
| JPS62283960A (en) | Di- and tetrahydroisoquinoline derivative and manufacture | |
| US4124712A (en) | Ergot peptide alkaloid derivatives | |
| Kanaoka et al. | Polyphosphate Ester as a Synthetic Agent. VI. The Bischler-Napieralski Reaction of Tryptamine and Tryptophan Derivatives by Means of Polyphosphate Ester | |
| US4088647A (en) | Pyrazino (1,2,3-ab)-β-carboline derivatives and salts thereof and method of preparing same | |
| US3666762A (en) | 2{40 {62 -ISOPROPYL-5{40 {60 -n-PROPYL-9,10-DIHYDRO-ERGOPEPTINES | |
| US4362739A (en) | Pyrrolo(2,3-d)carbazole derivatives, compositions and use | |
| GB1569251A (en) | Pyridobenzodiazepines | |
| US3901891A (en) | 13-bromolysergic acid compounds | |
| US4057551A (en) | Indolo[2,3-a]quinolizines | |
| GB1590149A (en) | Ergot alkaloid peptide derivatives | |
| US3944582A (en) | Carbamates of ergolines | |
| US3681355A (en) | Ergonarcarnines | |
| US4057550A (en) | Nitrogen-containing polycyclic compounds | |
| US3772299A (en) | P'-alkoxy-ergotamines | |
| IE46385B1 (en) | N-9, 10-dihydrolysergyl-m-aminobenzinc acid amides and related compounds | |
| US4076715A (en) | 13-Bromo lysergic acid compounds | |
| EP0138490B1 (en) | 4-alkyl methylenedioxy-2-1[H]-quinazolinones | |
| CA1051900A (en) | 1-hydroxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo(2,3-a)quinolizine compounds | |
| CA1199638A (en) | Eburnane-oxime ethers, process for their preparation and pharmaceutical compositions containing them | |
| US4609657A (en) | Ergot peptide alkaloid derivatives, processes for their preparation and pharmaceutical compositions containing them |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed [section 19, patents act 1949] | ||
| PCNP | Patent ceased through non-payment of renewal fee |