GB2057448A - (20S)-3 alpha -(Aminoacetylamino)- 5 alpha -pregnan-20-ol and its Acid Addition Salts - Google Patents
(20S)-3 alpha -(Aminoacetylamino)- 5 alpha -pregnan-20-ol and its Acid Addition Salts Download PDFInfo
- Publication number
- GB2057448A GB2057448A GB8026312A GB8026312A GB2057448A GB 2057448 A GB2057448 A GB 2057448A GB 8026312 A GB8026312 A GB 8026312A GB 8026312 A GB8026312 A GB 8026312A GB 2057448 A GB2057448 A GB 2057448A
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- United Kingdom
- Prior art keywords
- compound
- process according
- acid
- pregnan
- group
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
Abstract
The novel title compounds are prepared from funtumidine by N- acylation and salification, and are used in the treatment of auto- immunity diseases.
Description
SPECIFICATION
Derivative of 5-a-pregnan-20-ol and its Acid
Addition Salts
The present invention relates to a new derivative of 5-pregnan-20-ol and its acid addition salts, as well as the preparation of this derivative and its salts, their use as medicaments and compositions containing the same.
According to the invention there is provided (20S)-3-(aminoacetylamino)-5-pregnan-20-ol or an acid addition salt thereof with an organic dr a mineral acid.
As examples of acid addition salts there may be mentioned salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic or aspartic acid, an alkanesulphonic acid such as methanesulphonic acid or an arylsulphonic acid such as benzenesulphonic acid.
(20S)-3a-(aminoacetylamino)-5a-pregnan- 20-oils a new compound which has never been described until now. (20S)-3a- (aminoacetylamino)-5-pregnan-20-ol as well as its acid addition salts with pharmaceuticallyacceptable acids shows interesting pharmacological properties as is illustrated by the results of tests given hereinafter in the experimental portion; these compounds, in particular, stimulate the action of the immune defence system in animals including man, potentiating especially the production of IgE (ivmunoglobulins E).
(20S)-3-(aminoacetylamino)-5-pregnan- 20-ol as well as its acid addition salts with pharmaceutically-acceptable acids can, therefore, be used for the treatment of auto-immunity diseases resulting from a deficiency in certain lymphocytes, whether they be non-specific diseases of the connective tissue of a given organ such as, for example, rheumatoid arthritis or systemic lupus erythematosus, or whether they be specific diseases of an organ such as the thyroiditis pymphygus or haemolytic anaemia.
The compounds of the invention thus can be used as adjuvant treatment in antibiotherapy and in anti-cancer chemotherapy.
Accordingly, the invention includes the use of (20S)-3-(aminoacetylarnino)-5a-pregnan-20-ol as well as its acid addition salts with pharmaceutically-acceptable acids as a medicament in the above-mentioned treatments.
The invention also includes a pharmaceutical composition, which composition comprises, as active principle, at least one compound according to the invention, together with a pharmaceutically-acceptable excipient or carrier.
The compositions of the invention can be administered by a variety of routes, especially by an oral, rectal or parenteral route.
Moreover, the compositions may be solid or liquid and may be presented in a wide variety of pharmaceutical forms such as those currently used in human medicine, for example, plain or
sugar-coated compressed tablets, gelatin
capsules, granules, suppositories and injectable
preparations, which may be prepared according to
known methods.
The active principles or principles of the
compositions may be mixed with such excipients
as are usually employed in pharmaceutical
compositions, and the excipient used may be solid or liquid as appropriate to the pharmaceutical form chosen. The excipient may be selected from
a wide range of organic and inorganic solids, and
aqueous and non-aqueous liquids, of which
examples include talc, gum arabic, lactose, starch,
magnesium stearate, fatty substances of animal or vegetable origin such as cocoa butter, paraffin derivatives or glycols. These excipients may be compounded with or there may be used alone one
or more wetting, dispersing or emulsifying agents
and/or one or more preservatives.
The dose administered may be varied
according to the complaint treated, the person
concerned, the route of administration and the
compound used. Thus the dose may be, for
example, of from about 1 to about 100 mg per day, when administered orally in an adult human
being.
The invention also provides a process for preparing a compound according to the invention, which process comprises reacting funtumidine or (20S)-3a-amino-5a-prngnan-20-ol with an amino acid of the general formula:
in which R represents as easily-cleavable protective group, especially one easily cleavable by hydrogenation, to obtain a compound of the general formula:
and subjecting the compound of formula Ill to the action of an agent for cleaving the group R, to obtain a compound of the formula:
which is subjected, if desired, to the action of an acid to form a salt thereof.
As an easily-cleavable protective group R there may be used, for example, the carbobenzyloxy group or the carbotert-butyloxy group. In an especially preferred process the protective groups
R is the carbobenzyloxy group.
In the process of the invention the reaction between (20S)-3-amino-5a:-pregnan-20-ol and the amino acid of formula Il preferably takes place in the presence of a condensation agent. The aim
of the condensation agent, is of course, to activate the acid function of the amino acid of formula 11. As condensation agent there may be used a carbodiimide of the general formula: R1-N=C=N-R2 in which R1 and R2, which may be the same or different, represent an alkyl radical containing from 1 to 8 carbon atoms, optionally bearing a dialkylamino radical, or R, and R2 represent a cycloalkyl radical.
As examples of the above condensation agents there may be mentioned, for example, dicyclohexylcarbodiimide or 1-ethyl-3-(3- dimethylamino-propyl)-carbodiimide of which the
latter is a preferred agent.
As a condensation agent there may also be
used an alkyl chloroformate such as, for example,
methyl or ethyl chioroformate, as well as an alkyl
pyrophosphite such as, for example, ethyl
pyrophosphite.
As cleaving agent, it is preferred to use hydrogen in the presence of palladium.
The formation of salts can be effected according to standard techniques, for example, by the addition of the appropriate acid to the basic compound.
The starting material used in the process of the invention, namely (20S)-3a-amino-5ar- pregnan-20-ol, is a known product (see Merck Index, 9th edition, heading 4144).
The following examples illustrate the invention without, however, limiting it.
Example 1: (20S)-3-(aminoacetylamino)-5-pregnan-20- ol (Hydrochloride Salt and Base).
Stage A: (20S)-3a!-(benzyloxycarbonylaminoacetyl- amino)-5a-pregnan-20-ol 5.2 g of (20S)-3a-amino-5 < Z-pregnan-20-ol and 5.2 g of N-carbobenzyloxyglycine were dissolved in 1 50 cc of chloroform and 1 5 cc of pyridine. The solution was agitated in an ice-bath under nitrogen and 3.9 g of 1-ethyl-3-(3dimethylaminopropyl)-carbodiimide hydrochloride were added. At the end of one hour there were then added 310 mg of 1 -ethyl-3-(3 dimethylaminopropyl)-carbodiimide hydrochloride, the agitation being maintained for half-an-hour in the ice-bath and then the mixture being diluted with a saturated solution of sodium acid carbonate.The insoluble portion was then filtered off, washed separately with a solution of sodium bicarbonate, with water, with normal hydrochloric acid and finally with water, then dried at 500C. There were thus recovered 5.1 g of insoluble product.
The chloroform phase was separated from the filtrate, then washed with water, with normal hydrochloric acid and finally with water, dried and distilled to dryness. There were thus obtained 4.6 g of semi-crystalline residue. The insoluble product (5.1 g) and the semi-crystalline residue (4.6 g) were combined and made into a paste at reflux with 25 cc of methanol. The paste was then chilled, and the solid separated, washed with methanol and dried at 500C to provide 7.05 g of the desired product, melting at 250 to 2520C.
This product was used as such in the following stage, while an analytical sample obtained by recrystallisation from acetic acid had a melting point of 2540C.
Stage B: (20S)-3ar-(aminoacetylamino)-5a-pregnan ol Hydrochloride.
7 g of the product obtained in Stage A were dissolved with heating in 1 50 cc of acetic acid.
The solution thus obtained was agitated under nitrogen bubbled into it, allowed to cool to about 450C and 700 mg of 10% palladium on charcoal were added thereto. The bubbling-in of nitrogen was then replaced by slight bubbling-in of
hydrogen. At the end of one hour a current of
nitrogen bubbled into it, allowed to cool to about
hydrogen and the bubbling continued for 1 5 minutes. The catalyst was then filtered off and rinsed with acetic acid and the filtrate evaporated to dryness. The thus-obtained crystalline product was then dissolved in 50 cc of methanol and the desired salt precipitated by the addition of 4 cc of a 5.5 N solution of hydrochloric acid in ethanol.
The thus-obtained suspension was diluted with
50 cc of absolute ethanol, concentrated by half and left'four one night at about +50C. The solid product was then separated by filtration, washed with ethanol and dried, giving 4.43 g of the desired product.
The filtrate, mixed with 0.5 cc of a 5.5 N
solution of hydrochloric acid in ethanol and
concentrated to a small volume, provided a
second yield of 0.35 g of the desired product The
pure product, melting at 271 0C, was obtained
after recrystallisation from 80% ethanol.
/a/20=+l9.S+ 10(1%, pyridine containing 10% of water).
Stage C:
Preparation of the Base
The crude hydrochloride obtained in Stage B was dissolved in hot water. By the addition of an
excess of 2N sodium hydroxide the base was
precipitated. This was separated, washed with water, dried and recrystallised from methanol.
The pure base thus-obtained had a melting point of 269 C and/r/D =+25 +1 (1%, pyridine containing 10% of water).
Example 2:
Pharmacological Study of the Hydrochloride
Salt of Example 1, Hereinafter Called Product
A, using LEVAMISOLE as a Comparison
Compound
LEVAMISOLE is a well-known compound (see Merck Index, 9th edition, heading 8949) which has immuno-regulating properties, see Cancer
Research 35927 (1975) or New England Journal of Medicine 289(21)1148(1973).
A-Potentiation of the Production of IgE
Female mice, weighing 28 to 30 g, were immunised by the sub-cutaneous route with ovalbumin mixed with alumina on days 0 and 14 and their serum sampled on day 21 to determine the IgE antibodies formed. The respective amounts of antigen (ovalbumin) and adjuvant (alumina) injected were selected so that the production of antibodies was minimal.
The compounds studied were administered by the subcutaneous route three hours before the first immunisation.
The determination of the IgE's was carried out by means of the passive skin anaphylaxia test.
This test consists in causing in an animal, by intravenous administration of the antigen, an antigen-antibody reaction in a skin area where previously there have been injected antibodies prepared in another animal with the same antigen. This reaction is made visible due to a dye injected at the same time as the antigen: there is an appearance, at the point of injection of the antibodies, of a coloured spot, demonstrating the bursting of the sensitised cells and the increase in the capillary permeability resulting therefrom. The greatest dilution of the serum which gives a spot having a diameter of 11 to 13 mm in all the animals were investigated. The equivalent dilution of the serum was injected intradermally at a volume of 0.1 ml into male rats weighing, on
average, 250 g, in the region of the back.Forty
eight hours later the animals receive
intravenously 0.5 ml of a solution containing 0.5% of ovalbumin and 1% of Evans blue in an
isotonic solution of sodium chloride. Thirty
minutes after this injection they were sacrificed
by bleeding and the diameter of the blue spot was
measured on the turned-back skin.
The results obtained were as follows:
Product a 0.5 mg/kg sub-cutaneously
Levamisole 20 mg/kg sub-cutaneously
Conclusion: according to this test Product A is
much more immunostimulating than Levamisole.
B-Chronic Arthritis Caused by the Adjuvant
The injection of Freund-type adjuvant (Mycobacterium butyricum at 6 mg/ml in Bayol 55) into a rear paw causes in the rat of primary inflammatory lesion then, after a period of latency of 1 3 to 1 5 days, the initiation of secondary inflammations affecting the non-injected rear paw as well as the front paws, the tail and the ears.
This secondary arthritis can be compared with human rheumatoid arthritis since the intervention of auto-immunity reactions is admitted among its determining factors.
Male rats, aged 42 to 50 days, received by intraplantar injection 0.10 ml of Freund adjuvant.
The treatment began on the day of the injection of the adjuvant and lasted until the sacrifice of the animals on the 17th day.
The criteria of estimation of the activity of the substances are, in general: - the increase in weight of the animals, always restrained more or less proportionally to the intensity of the arthritis; - the increase in volume of the injected and non-injected rear paws with reference to the average volume of the corresponding paws of the normal controls; - the arthritis of the front paws, of which the too-small volume does not lend itself to plethysmometric measurement and is, therefore, marked subjectively from 0 to 3 according to the intensity of the inflammation; - the arthritis of the ears and of the tail, marked 1 or 0 according to the presence or the absence of nodosities.
In the present test the effect on the secondary inflammations, that is to say on the arthritis of the non-injected rear paw, the arthritis of the front paws and the inflammations of the ears and of the tamil, was observed in particular.
The active dose which reduced the secondary inflammations by at least 50% was investigated and the results were as follows:
Product A active dose 1 mg/kg (subcutaneously)
Levamisole active does 50 mg/kg (orally)
Conclusion: product A is, therefore, very active
against the secondary phenomena of arthritis
caused by the adjuvant whereas a very high
subtoxic dose of Levamisole is necessary to
establish a comparable effect.
Example 3:
Example of a Pharmaceutical Composition
Compressed tablets were prepared,
corresponding to the following formula:
Hydrochloride of Example 1 10 mg
Excipient (talc, starch,
magnesium stearate q.s. for 1 compressed
tablet
Claims (14)
1. (20S)-3 a:-(aminoacetyla mino)-5-pregnan- 20-ol or an acid addition salt thereof with an
organic or a mineral acid.
2. A compound according to claim 1 in the
form of a salt formed with hydrochloric,
hydrobromic, hydroiodic, nitric, sulphuric,
phosphoric, acetic, formic, benzoic, maleic,
fumaric, succinic, tartaric, citric, oxalic, glyoxylic,
aspartic, an alkanesulphonic or an arylsulphonic
acid.
3. A process for preparing a compound as
defined in claim 1, which process comprises reacting (20S)-3a-amino-5-pregnan-20-ol with an amino acid of the general formula:
in which R represents an easily-cleavable protective group, to obtain a compound of the general formula:
and subjecting the compound of formula Ill to the action of an agent for cleaving the group R, to obtain a compound of the formula:
which is subjected, if desired, to the action of an acid to form a salt thereof.
4. A process according to claim 3, wherein the protective group is one cleavable by hydrogenation.
5. A process according to claim 4, wherein the protective group R is the carbobenzyloxy group.
6. A process according to any one of claims 3 to 5, wherein the reaction between (20S)-3- amino-5cg-pregnan-20-ol and the amino acid of formula ll takes place in the presence of a condensation agent.
7. A process according to claim 6, wherein the condensation agent is a carbodiimide of the general formula: R1-N=C=N-R2 in which R1 and R which
2' h may be the same or different, represents an alkyl radical containing from 1 to 8 carbon atoms, optionally bearing a dialkylamino radical, or R, and R2 represent a cycloalkyl radical.
8. A process according to claim 7, wherein the carbodiimide used is 1 -ethyl-3-(3-dimethylamino- propyl)-carbodiimide.
9. A process according to any one of claims 4 to 8, wherein the group R is cleaved using hydrogen in the presence of palladium.
10. A process according to claim 3 and substantially as hereinbefore described with reference to Example 1.
11. A compound as defined in claim 1 when prepared by a process according to any one of claims 3 to 10.
12. A pharmaceutical composition, which composition comprises, as active principle, at least one compound according to any one of claims 1, 2 or 11, together with a pharmaceutically-acceptable excipient or carrier.
13. A composition according to claim 12 substantially as hereinbefore described specifically.
14. A compound according to any one of claims 1,2 or 11 or a composition according to claim 12 or claim 13 when used as a medicament in the treatment of auto-immunity diseases.
1 5. A compound according to any one of claims 1,2 or 11 or a composition according to claim 1 2 or claim 1 3 when used as a medicament substantially as hereinbefore described specifically.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR7920840A FR2463777A1 (en) | 1979-08-17 | 1979-08-17 | NOVEL DERIVATIVES OF 5A-PREGNAN-20-OL, PROCESS FOR PREPARING THEM AND THEIR APPLICATION AS MEDICAMENTS |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2057448A true GB2057448A (en) | 1981-04-01 |
GB2057448B GB2057448B (en) | 1983-05-18 |
Family
ID=9228902
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8026312A Expired GB2057448B (en) | 1979-08-17 | 1980-08-13 | (20s)-3-(aminoacetylamino)-5-pregnan-20-ol and its acid addition salts |
Country Status (19)
Country | Link |
---|---|
JP (1) | JPS5659800A (en) |
AT (1) | AT373902B (en) |
AU (1) | AU529528B2 (en) |
BE (1) | BE884794A (en) |
CA (1) | CA1140111A (en) |
CH (1) | CH646182A5 (en) |
DE (1) | DE3031161A1 (en) |
DK (1) | DK352380A (en) |
ES (1) | ES494256A0 (en) |
FI (1) | FI68844C (en) |
FR (1) | FR2463777A1 (en) |
GB (1) | GB2057448B (en) |
HU (1) | HU180376B (en) |
IE (1) | IE50226B1 (en) |
IT (1) | IT1145382B (en) |
NL (1) | NL8004600A (en) |
PT (1) | PT71700B (en) |
SE (1) | SE446006B (en) |
ZA (1) | ZA804473B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2494698A1 (en) * | 1980-11-21 | 1982-05-28 | Roussel Uclaf | NOVEL SUBSTITUTED 3-AMINO STEROID DERIVATIVES, THEIR SALTS, PREPARATION METHOD, MEDICAMENT APPLICATION AND COMPOSITIONS COMPRISING THE SAME |
FR2515188A1 (en) * | 1981-10-27 | 1983-04-29 | Roussel Uclaf | NOVEL 3-AMINO-PREGN-5-ENE DERIVATIVES, THEIR SALTS, PREPARATION METHOD, MEDICAMENT APPLICATION AND COMPOSITIONS COMPRISING THE SAME |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3196169A (en) * | 1964-11-03 | 1965-07-20 | American Home Prod | Aminoacyl aminosteroids |
-
1979
- 1979-08-17 FR FR7920840A patent/FR2463777A1/en active Granted
-
1980
- 1980-07-22 SE SE8005309A patent/SE446006B/en not_active IP Right Cessation
- 1980-07-24 ZA ZA00804473A patent/ZA804473B/en unknown
- 1980-08-06 FI FI802462A patent/FI68844C/en not_active IP Right Cessation
- 1980-08-13 GB GB8026312A patent/GB2057448B/en not_active Expired
- 1980-08-14 BE BE0/201765A patent/BE884794A/en not_active IP Right Cessation
- 1980-08-14 IT IT49507/80A patent/IT1145382B/en active
- 1980-08-14 ES ES494256A patent/ES494256A0/en active Granted
- 1980-08-14 PT PT71700A patent/PT71700B/en unknown
- 1980-08-14 NL NL8004600A patent/NL8004600A/en not_active Application Discontinuation
- 1980-08-15 JP JP11189680A patent/JPS5659800A/en active Pending
- 1980-08-15 CH CH616280A patent/CH646182A5/en not_active IP Right Cessation
- 1980-08-15 CA CA000358412A patent/CA1140111A/en not_active Expired
- 1980-08-15 IE IE1737/80A patent/IE50226B1/en unknown
- 1980-08-15 HU HU80802040A patent/HU180376B/en not_active IP Right Cessation
- 1980-08-15 AU AU61486/80A patent/AU529528B2/en not_active Ceased
- 1980-08-15 DK DK352380A patent/DK352380A/en not_active Application Discontinuation
- 1980-08-18 DE DE19803031161 patent/DE3031161A1/en active Granted
- 1980-08-18 AT AT0420880A patent/AT373902B/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
IE50226B1 (en) | 1986-03-05 |
FR2463777A1 (en) | 1981-02-27 |
IT1145382B (en) | 1986-11-05 |
DE3031161C2 (en) | 1988-09-29 |
CA1140111A (en) | 1983-01-25 |
SE8005309L (en) | 1981-02-18 |
PT71700B (en) | 1982-01-22 |
BE884794A (en) | 1981-02-16 |
JPS5659800A (en) | 1981-05-23 |
ATA420880A (en) | 1983-07-15 |
FI802462A (en) | 1981-02-18 |
AT373902B (en) | 1984-03-12 |
DE3031161A1 (en) | 1981-03-26 |
HU180376B (en) | 1983-02-28 |
DK352380A (en) | 1981-02-18 |
ES8103760A1 (en) | 1981-03-16 |
NL8004600A (en) | 1981-02-19 |
FR2463777B1 (en) | 1983-04-29 |
FI68844B (en) | 1985-07-31 |
ZA804473B (en) | 1981-07-29 |
PT71700A (en) | 1980-09-01 |
CH646182A5 (en) | 1984-11-15 |
FI68844C (en) | 1985-11-11 |
AU6148680A (en) | 1981-02-19 |
SE446006B (en) | 1986-08-04 |
IE801737L (en) | 1981-02-17 |
ES494256A0 (en) | 1981-03-16 |
IT8049507A0 (en) | 1980-08-14 |
AU529528B2 (en) | 1983-06-09 |
GB2057448B (en) | 1983-05-18 |
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Legal Events
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PCNP | Patent ceased through non-payment of renewal fee |