IL32767A - A hydrazide and its acid addition salts - Google Patents
A hydrazide and its acid addition saltsInfo
- Publication number
- IL32767A IL32767A IL32767A IL3276769A IL32767A IL 32767 A IL32767 A IL 32767A IL 32767 A IL32767 A IL 32767A IL 3276769 A IL3276769 A IL 3276769A IL 32767 A IL32767 A IL 32767A
- Authority
- IL
- Israel
- Prior art keywords
- hydrazide
- serine
- acid addition
- derived
- group
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/72—Hydrazones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C243/34—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a carbon skeleton further substituted by nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
32767/2 ¾> ο*»ηχηιπ nioo 'n ar .i Hi n A hydrazide and its acid addition salts SPARAMEDICA A.G.
C. 51064 RAN 4007/14 The present invention relates to the novel hydrazide of the formula which hydrazide is derived from L-serine, as well as to aoid addition salts thereof. The invention also relates to a prooess for the manufacture of the above compounds and to their use.
The term "derived from L-serine" denotes that the compounds ooncerned have a sterio configuration corresponding to that of L-serine.
The prooess in accordance with the invention is characterised in that a compound of the formula which oompound is present in the form of the raoemate or of the antipode derived from L-serine, or an acid addition salt thereof, is hydrogenated, or in that in a compound of the general formula wherein R^, R≥ and R^ signify hydroxy groups or groups convertible into hydroxy groups and ^ signifies the oc-amino-P-hydroxyethyl group l-CH( H2)CH20H] or a group convertible into the a-amino-P-hydroxyethyl group, at least one of the substituents R^, R2> R-j and R^ being different from the hydroxy group or from the a-amino-P-hydroxyethyl group, which compound is present in the form of the racemate or of the antipode derived from L-serine, or in an acid addition salt of such a compound, the group or groups convertible into the hydroxy group and/or into the a-amino-P-hydroxyethyl group are converted into the hydroxy group or into the a -amino β-hydroxyethy1 group, in that the antipode derived from L-serine is isolated from a raoemate thus obtained, and in that a base thus obtained is converted into an acid addition salt, if desired.
The groups convertible into hydroxy groups designated in the above formula lib with R^, Rg and are preferably benzyloxy groups. However, these groups can also' be acetal groupings which are derived from acetaldehyde, acetone or , tetrahydropyran, e.g. a-methoxy-ethoxy, a-methoxy-isopropoxy and tetrahydropyranyloxy. These groups can be converted into hydroxy groups in a manner known per se by hydrogenolysis, preferably by means of catalytic hydrogenation, e.g. with noble-metal catalysts such as palladium and platinum cata- lysts. Other groups which are convertible into the hydroxy group are e.g. acyloxy groups such as lower alkanoyloxy groups, which can be converted into the hydroxy group by hydrolysis.
Suitable groups R^ convertible into the a-amino-β· hydroxyethyl group are particularly the following: a-benzhydrylamino-β-hydroxyethyl [(C^HC)0 CH-NH-CH-CH 0H] , Ό 5 d | . £- a-azido-p-hydroxyethyl (N^-CH-CI^OH) , a-nitro-P-hydroxyethyl (O^N-CH-CH-OH) , a-phenylazo-p-hydroxyethyl (C6H5-N=N-CH-CH?OH) , a-hydroximino-β-hydroxyethyl (H0N=C-CH 0H) , a-phenylhydrazono-P-hydroxyethyl ( CgH,- -NH-N=C-CH20H ) .
The above groups can be converted into the oc-amino-β- hydroxyethyl group by hydrogenation according to procedures known per se. The hydrogenation can be effected catalyrtically as well as by means of chemical reducing agents. As catalysts there may be used noble-metal catalysts such as palladium and platinum catalysts, or nickel or cobalt catalysts.
Other groups convertible into the a-amino-β-hydroxy- ethyl group are e.g.: cx-formylamino-p-hydroxyethyl (CHO H-CH-CHgOH ) , oc-trifluoroacetylamino- -hydroxyethyl (CF^-CONH-CH-CI^OH ) , a-tritylamino- -hydroxyethyl [ ( ] , a-alkoxycarbonylamino- -hydroxyethyl (alkyl-OCONH-CH-CHgOH ) and a-phthalimido- -hydroxyethyl These groups can be converted into the a-amino-P-hydroxy ethyl groups by hydrolysis according to procedures known per se. Thus the hydrolysis of the a-formylamino-β-hydroxy- ethyl group can be effected by means of dilute alcoholic hydrochloric acid, whereas the hydrolysis of the 2-trifluoro- acetylamino-β-hydroxyethyl group may also be effected by means of a dilute aqueous ammonia solution. The conversion of the a-phthalimido^-hydroxyethyl group can be effected by means of hydrazine.
Other groups convertible into the a-amino-^-hydroxy-ethyl group are: These groups can be converted into the a-amino-β-hydroxy ethyl group by reaction with ammonia in the presence or absence of a solvent .
Other groups convertible into the a-amino-P-hydroxyethyl group are: 2-carboxamido^-hydroxyethyl (HgNCO-CH-CHgOH) , a-carbohydrazido- -hydroxyethyl (H2N- H-C0-
A further group which is convertible into the a-amino-β-hydroxyethyl group is the a-carboxy-oc-amino^-hydroxyethyl group which can be converted into the former group. by decarboxylation, e.g. by mild heating.
The hydrogenation to be carried out in accordance with the process of the present invention when using starting materials of formula Ila is preferably effected catalytically. for example by means of a platinum oxide or palladium-charcoal catalyst.
When a compound of formulae Ila and lib whose configuration corresponds to that of L-serine is used as the starting material, correspondingly configured end-products are obtained directly. This embodiment of the process is preferred. When using a racemic starting material of formulae Ila and lib, the antipode derived from L-serine must be isolated from the racemate of formula I obtained. This can be effected in the usual manner by means of an optically active acid, for example with tartaric acid or camphersulphonic acid.
When the base is obtained as the process product, this can be converted into an acid addition salt with an inorganic or an organic acid, for example into the hydrochloride, the sulfate, the acetate, the oxalate etc. The salts are preferred over the base because of their greater stability.
A preferred embodiment of the process in accordance with the invention consists in catalytically hydrogenating an acid addition salt of N -L-serine-N -(2,3, -trihydroxy-benzyli-dene)-hydrazide, especially the hydrochloride, preferably using a palladium-charcoal catalyst. In doing this, the corres- 1 2 ponding salt of N -L-serine-N -(2,3, -trihydroxybenzyl)-hydrazide is obtained directly.
The same product can also be obtained by catalytically hydrogenating an acid addition salt of N 1-L-serine-N2-(2,3,4-tribenzyloxy-benzylidene) -hydrazide, preferably using a palladium-charcoal catalyst. In this case, hydrogenolysis of the benzyloxy groups takes place first and subsequently hydro-genation of the benzylidene group occurs., a salt of N1-L-serine- N -(2,3, -trihydroxybenzyl) -hydrazide being obtained.
The compounds of formula Ila and lib and their salts used as starting materials in the process in accordance with the invention can be obtained according to methods which are known per se. The compound of formula Ila is obtained by reaction of an acid addition salt of L-serine hydrazide with 2,3, -trihydroxybenzaldehyde. Starting materials of formula lib can be obtained by reaction of a correspondingly substituted serine hydrazide with a correspondingly substituted benzaldehyde and subsequent hydrogenation of the benzylidene compound obtained, e.g. by means of a platinum catalyst.
The compounds obtained according to the present invention (the hydrazide of formula I derived from L-serine, and its acid addition salts) display pharmacological activity, that is, they possess a decarboxylase-inhibiting activity.
However, these compounds are of particular interest in that, in combination with L-dopa, they represent outstanding agents for the treatment of Parkinsonism. Moreover, in combination with L-dopa they act antidepressively and the antidepressive activity of tricyclic amines, for example of imipramlne, is also potentiated by this combination.
It has been determined that in rats small doses 1 2 ( 12 mg/kg) of N -L-serine-N -(2,j5,4-trihydroxybenzyl)-hydrazide hydrochloride augment for at least 4 hours the enhancement of L-3, -dihydroxy-phenylalanine (L-dopa) in the blood and in the brain induced by intraperitoneal or oral administration of this amino acid. At the same time, the increase of catecholamines (CA) and their metabolites, the phenol-carbox lie acids, is strongly reduced in the blood and other peripheral organs (heart, kidneys, spinal cord), but considerably augmented in the brain. As a consequence of the decrease of the catecholamine content in the periphery, the peripheral adrenergic stimulation is also diminished. On the other hand, the catecholamine depots in the extrapyramidal centres of the brain are extraordinarily strongly enhanced.
It is assumed that this effect is the consequence of a relatively selective inhibition of the decarboxylase by the N^-L-serine-(2,3, -trihydroxybenzyl ) -hydrazide hydrochloride in the extracerebral organs. As a consequence of the enhanced dopa concentration in the blood, larger amounts of amino acid get into the brain, where the decarboxylation to catecholamines takes lace because . the cerebral decarboxylase is practically uninhibited. This seleotive activity of L-seryl-(2,3,4-trihydroxybenzyl) -hydrazide is indeed the consequence of a very low capability of this compound of penetrating into the brain. Thus, the decarboxylase activity in the brain of animals to which L-seryl-(2,3, -trihydroxybenzyl)-hydrazide hydrochloride has been injected is not markedly inhibited up to doses of 50 mg/kg, whilst in the heart an about 80 inhibition is already observed at a dosage of 25 mg/kg. On the other hand, when it is added to homogenised tissue, the compound causes the same decarboxylase inhibition both in the brain and in the heart .
To determine the activity on the enhancement of the catecholamine content in the brain Induced by dopa, N^"-L-se- 2 rine-N -(2,3, -trihydroxybenzyl) -hydrazine hydrochloride was administered orally to the experimental animals (rats) in doses of 3-100 mg/kg. Thirty minutes later, 3 mg/kg of L-dopa were administered orally and the animals were killed 1 hour later.
It was determined that 12-24 mg/kg of the hydrazide induced the maximal enhancement of the catecholamines in the rat brain. This value is approximately 60 times higher than that which is obtained on the administration of L-dopa alone.
For the purpose of antiparkinson treatment, as well as for the purpose of treating depressive states, the combination of the compounds obtainable according to the process in w th the invention the h drazide of formula I 32.767/2" derived from L-serine, and its acid addition salts) with L-dopa can be administered both as an aotual combination in a single dosage form or separately in two dosage forms. Sinoe it has been found to be expedient that 'the L-dopa only be released in the body after the hydrazide, that is, preferably, about 5O-60 minutes after the hydrazide, in the' case of administration of a single dosage form the L-dopa should be present in this in such a form that it is only released after the hydrazide. Such a combination with delayed dopa release can, for example, oonsist of a nucleus of L-dopa with a coating resistant to gastric, juice. This nucleus can display an outer layer which contains the hydrazide, or the hydrazide, in the form of a granulate, oan be,' incorporated in a capsule together with the L-dopa nuoleus. In the case of parenteral japplication of the combination, the hydrazide is expediently first administered , , intramusoularly and, about 3Ο-6Ο minutes later, the L-dopa administered intravenously.
Of considerable significance is the quantitative ratio of hydrazide to L-dopa. This should amount to 0.5-2 parts by weight, preferably one part by weight, per part by weight of L-dopa. 225-600 mg of hydrazide and 450-600 mg of L-dopa (di- . vided into 3-4 administrations) are expediently applied daily.
The British patent specification No. 947»128 and the corresponding U.S. patent specification 3,178,476 disclose [(di- or trihydroxy)-benzyl]~hydrazides some of which are derived from D,I-serine, and their preparation, but they do not describe the oompound according to this invention. Also, the N-L-seryl-hydraalde of the present invention is an optically-active isomer whose properties diffr from the properties of the corresponding racemio N-seryl-hydrazide disclosed in the above publications.
The superiority of the compound of this invention over the aoresaid known compounds can be demonstrated by measurement of the L-dopa-induced increase of catecholamines In the brain of 5ats, by the administration oft 1) 12 mg/ ^-B.^ee-7l-H2-(2.3.4.trihyaroXybenZyX).hyaraal»e hydrochloride (Example 3 of the above British specification, compound A in the table below)? 2) an equimolar dose of Mi-I)?I^lanyl-H^-2,3,4-trihydroxybenayl)- hydrazine hydrochloride (Example 6 of the above British specification, compound B); and 3) a equimolar dose of H1-L-seryl-fl2-(2,3t4-trihydroxybenzyl)^ hydrazine hydrochloride according to the present invention (oompound G).
In the Table below, the potenoy of N^- eL-seryl-li2* (2,3,4-trihydroxybenzyl)*hydrazlne hydrochloride (oompound A) is rated as 100, and the potencies of the other two compounds are compared therewith.
C o m pro u n d A B C L-DOPA-induced Increase of catecholamines The Table shows that Compound C (according to the invention) possesses a better decarbox laae-inhibiting property than do the known compounds and B.
Example 1 21 g of li^-L^seri e-H^iatJf^trihydrox -bensylidene)-hydraside hydrochloride are suspended in 300 ml of methanol and hydrogenated by means of a palladium-oharooal catalyst, dissolution being effected with the uptake o 1700 ml of hydrogen.
After filtering off the catalyst, the filtrate is concentrated under reduced pressure, the resulting viscous residue is dissolved in a small quantity of ethanol and diluted with 600-700 ml of ethyl acetate, whereupon a powdery, amorphous precipitate is formed. This precipitate is filtered off, washed with acetic ester and ether and dried under reduced 1 2 pressure over phosphorus pentoxide. The N -L-serine-N - (2,3 , 4-trihydroxy-benzyl)rhydrazide hydrochloride thus obtained represents an amorphous powder, readily soluble in water, which decomposes at about 120° with effervescence. lcr.JD » -10° (c = 1; H≥0 ) ; + 18° (c = 1 ; dimethylformamide ) . 1 2 The N -L-serine-N - (2 ,3»^-trihydroxy-benzylidene)-hydrazide hydrochloride used in this case as the starting material can be obtained as follows: . g of 2 ,3* 4-trihydroxybenzaldehyde are dissolved in 200 ml of boiling water, whereupon 15 * 2 g of L-serine-hydrazide hydrochloride are added to and dissolved in the resulting solution. The solution is concentrated under re-deced pressure and the water is gradually displaced by portion-wise" addition of ethanol. The resulting crystals- are separated from the mother liquor by filtration and washed with ethanol 1 2 and ether. N -L-Serine-N - (2 , 3* -trihydroxy-benzylidene)-hydrazide hydrochloride of melting point 260-265° is obtained. [
Example 2 29 g of N -L-serine-N -(2,3j4-tribenzyloxy-benzylidene)-hydrazide acetate are suspended In 300 ml of methanol and hydrogenated using a palladium-on-carbon catalyst. After 4.6 litres of hydrogen are taken up, 6.1 ml of benzyl chloride are added and the mixture is further hydrogenated until hydrogen uptake ceases again, whereupon the catalyst is removed by filtration and the solution concentrated under reduced pressure. The reaction product is then precipitated by dilution with ethyl acetate. It is identical with the substance manufactured according to Example 1. 1 2 The N -L-serine-N -(2,3,4-tribenzyloxy-benzylidene)-hydrazide acetate used in this case as the starting material can be obtained as follows: 21.2 g of 2,3* 4-tribenzyloxy-benzaldehyde are dissolved in 300 ml of boiling alcohol and treated with a solution of 7.2 g of L-serine-hydrazide hydrochloride and 7.1 ml of tri-ethylamine in 30 ml of water. The mixture is boiled at reflux for 2-3 hours and allowed to cool. The resulting crystals are separated from the mother liquor by filtration and washed with 1 2 alcohol and ether. The N -L-serine-N :-(2,3> -tribenzyloxy-benzylidene)-hydrazide acetate thus obtained melts at 128-130°.
Example 3 hydrazide-hydroChloride were dissolved in 500 ml of methanol, and 50 g of potassium bicarbonate were carefully added in small portions into the solution under an atmosphere of nitrogen. The mixture was then boiled for 2-3 hours. The precipitated inorganic salts were separated by filtration of the boiling solution, the filtrate was cooled and. acidified by the addition of methanolic hydrochloric acid to a pH of about 4-5. The precipitated potassium chloride was separated from the solution and the latter was evaporated to dryness under reduced pressure. The amorphous powdery residue consisted of J^-.0-serine-ii2-(2,3,4-trihydroxy-ben2syl)-hydrazide hydrochloride, which decomposes with foaming at 120*0. /a 7 = -10° (e & 1 In water) D (3- - i° a 1 i dimethylformamlde).
D The ^-L-eerine-N2-(2,3,4«rtriacetoxy*benzyl)-hydrazide hydrochloride used as starting material In the above process can be prepared, e.g. as followst .5 g of L-serine-hydrazide hydrochloride and 28 g of 2,3,4-trlacetoxy-benzaldehyde (prepared by the reaction of pyro-gallolaldehyde with acetic anhydride in boiling ethyl ether in the presence of potassium carbonate, m.p. 90-91°C) were introduced into 600 ml o methanol. The compound N -.*-serlne-N^-(2,3* 4-triacetoxy-benzylidene)-hydrazide hydrochloride which formed as an intermediate was hydrogenated on a palladium-charcoal catalyst until 1 mol of hydrogen was absorbed. The catalyst w 3 removed by fil j*ation and the filtrate was evaporated to dryness under reduced pressure. The K -L-serine-N - (2,3,4-triacetoxy-benzyl)-hydrazlde hydrochloride residue could be used in the above mentioned Example 4 66ί«1 g of N *(N-benzyloxycarbonyl~: serine)-H -(2*3,4<- of methanol* 1 mol tribenzylpxy-benayljwhydrazide were suspended I 500 ml/o hydrochloric acid was added, and the solution was hydrogenated under normal hydrochloride which was o tained as an amorphous powder decomposes with foaming at 120°C.
B-^ * -10° (e » 1 in water) (a, 7 « +18° (c e? 1 in dlmethylformamide).
~ B 1 2 The H ·(N-benzyloxy-carbonyl-L-cserin©)-N -(2>3,4~ trifc^nzyloxy*benzyl)-hydrazide used as starting material can be prepared, e.g., as follows: 42.3 g of 2,3,4-tribenayloxy-benzaldehyde were dissolved in 1000 ml of ethanol. The solution was heated to boiling and 25.3 of benzyloxycarbonyl-Ii-Berine-hydras-asi were added thereto in small portions. Thereafter, 250-300 g of 5f» sodium amalgam were added in small portions to the boilin reaction mixture, whose pH as maintained at about 7·5-8 by the occasional additions of glacial acetic acid.
The reaction mixture was then cooled and after the mercury was separated therefrom, it was evaporated to dryness under reduced pressure. The residue was dissolved in water and the aqueous solution was extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate, and evaporated to dryness under reduced pressure.? The compound N1- (ϊϊ-benzyloxy-carbonyl-L-serine )·Η2- ( , 3 , ^tribenzyloxy-benzyl)-hydrazide which was obtained as a residue could be used in the above mentioned process without further purification., s Example A hard gelatin capsule in which the L-dopa component is present in delayed release form can be manufactured as follows: A core consisting of 50 mg of L-dopa, 8 mg of corn starch, 15 mg of lactose, 1.8 mg of talc and 0.2 mg of magnesium stearate is coated with a cellulose acetate phthalate lacquer in order to make it resistant to gastric juice.
A granulate is manufactured in the usual manner from 1 2 50 mg of N -L-serine-N -(2,j5, -trihydroxybenzyl)-hydrazide hydrochloride, 58.25 mg of mannitol and 2J.7 m of polyvinylpyrrolidone.
The coated nucleus and the granulate are incorporated into a hard gelatin capsule. 6 Example C a) Manufacture of tablets with L-dopa as the active tance: Tablets of the following composition are manufactured the usual manner: L-Dopa Lactose - Corn starch Magnesium stearate b) Manufacture of tablets with N -L-serine-N -(2,3,4-trihydroxybenzyl)-hydrazide hydrochloride as the active substance: Tablets of the following composition are manufactured in the usual manner: Active substance 150 mg Mannitol 200 mg Corn starch 120 mg Polyvinylpyrrolidone 15 mg Magnesium stearate 1.5 mg Talc I3.5 mg
Claims (3)
1. % Having now particularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we declare that what we claim is: 1. Process for the manufacture of the hydrazide of the formula which hydrazide is derived from L-serine, as well as of acid addition salts thereof, characterised in that a compound of the formula which compound is present in the form of the racemate or of the antipode derived from L-serine, or an acid addition salt thereof, is hydrogenated, or in that in a compound of the general formula wherein F^, R2 and R^ signify hydroxy groups or groups convertible into hydroxy groups and signifies the a-amino-P-hydroxyethyl group or a group convertible into the a-amino-P-hydroxyethyl group, at least one of the substituents R, , R , R.. 1 5 and R^ being different from the hydroxy group or from the a-amino-P-hydroxyethyl group, which compound is present in the form of the racemate or of the antipode derived from L-serine, or in an acid addition salt of such a compound, the group or groups convertible into the hydroxy group and/or into the a-amino-P-hydroxyethyl group are converted into the hydroxy group or into the a-amino-P- hydroxyethyl group, in that the antipode derived from L-serine is isolated from a racemate thus obtained, and in that a base thus obtained is converted into an acid addition salt, if desired.
2. Process according to Claim 1, characterised in 1 2 that an acid addition salt of N -L-serine-N -(2,3, -trihydroxy-benzylidene)-hydrazide, preferably the hydrochloride, is ca-talytically hydrogenated, preferably using a palladium-on-carbon catalyst . >. Process for the manufacture of the hydrazlde specified in Claim 1 and of acid addition salts thereof, as hereinbefore described, especially with reference to the foregoing examples 1 and 2. 4. Process for the manufacture of pharmaceutical preparations "having decarboxylase-inhibiting activity, characterized in that hydrazlde of the formula which hydrazlde is derived from L-serine, or an acid addition salt thereof is put into a medicinally acceptable form. 5. Process for the manufacture of pharmaceutical preparations suitable for the treatment of Parkinsonism and depressive states, characterised in that the hydrazlde of the formula which hydrazide is derived from L-serine, or an acid addition salt .thereof, is put. into a medicinally acceptable form together with L-dopa or an acid addition salt thereof. 6. Pharmaceutical preparation having decarboxylase-inhibiting activity, characterised in that it contains the hydrazide of the formula which hydrazide is derived from L-serine, or an acid addition salt thereof as the active ingredient. 7. Pharmaceutical preparation suitable for the treatment of Parkinsonism and of depressive states, characterized in that it contains the hydrazide of the formula which hydrazide is derived from L-serine, or an acid addition salt thereof in combination with L-dopa or an acid addition salt thereof as active ingredients. 8. Pharmaceutical preparation according to Claim 7, characterized in that the quantitative ratio of the hydrazide - razi e er art b 9. The hydrazide of the formula which hydrazide is derived from L-serine, as well as acid addition salts thereof, whenever prepared by the process claimed in Claim 1, 2 or 3, or by an obvious chemical equivalent thereof. 1 2 10. N -L-serine-N -(2,3, -trihydroxybenzyl)-hydrazide-hydrochloride, whenever prepared by the process claimed in Claim 1, 2 or , or1 by an obvious chemical equivalent thereof. ■J 32767/2 21 Hydrazides o the general formula wherein R^ Rg and signify hydroxy groups or groups convertible into hydroxy groups and R^ signifies the a-amino- β -hydroxyethyl group or a group convertible into the a -amino- β„ hydroxyethyl group, at least one of the substituents ^, Rg, ^ and ^ being different from the hydroxy group or from the α -amino- g -hydroxyethyl group, said hydrazides being derived from L-serine, as well as acid addition salts thereof, 12. The hydrazide of the formula HgOH which hydrazide is derived from L-serine, and acid addition salts thereof. 1
3. N^-Lserlne-N2-(2,3»4- ihydroxybenzyl)-hydrazide- hydrochlorid . For the A licants
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH1240368A CH554844A (en) | 1968-08-16 | 1968-08-16 | METHOD OF MANUFACTURING A HYDRAZIDE. |
Publications (2)
Publication Number | Publication Date |
---|---|
IL32767A0 IL32767A0 (en) | 1969-11-12 |
IL32767A true IL32767A (en) | 1973-01-30 |
Family
ID=4382677
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL32767A IL32767A (en) | 1968-08-16 | 1969-08-04 | A hydrazide and its acid addition salts |
Country Status (16)
Country | Link |
---|---|
JP (1) | JPS5114501B1 (en) |
AT (2) | AT299158B (en) |
BE (1) | BE737420A (en) |
CA (1) | CA958418A (en) |
CH (1) | CH554844A (en) |
CS (1) | CS162689B2 (en) |
DE (2) | DE1966821C3 (en) |
DK (1) | DK126776B (en) |
ES (1) | ES370500A1 (en) |
FR (2) | FR2015792B1 (en) |
GB (1) | GB1250279A (en) |
IE (1) | IE33519B1 (en) |
IL (1) | IL32767A (en) |
MY (1) | MY7300018A (en) |
NL (1) | NL6912320A (en) |
SE (1) | SE378242B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103951587A (en) * | 2014-04-11 | 2014-07-30 | 浙江耐司康药业有限公司 | Synthetic method for intermediate of benserazide hydrochloride |
WO2015197909A1 (en) | 2014-06-27 | 2015-12-30 | Fermion Oy | Process for the preparation of a crystalline polymorph of 2-amino-3-hydroxy-n'-(2,3,4-trihydroxybenzyl)propanehydrazide (benserazide) hydrochloride |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3065265A (en) * | 1957-07-04 | 1962-11-20 | Hoffmann La Roche | Amino acid hydrazides |
-
1968
- 1968-08-16 CH CH1240368A patent/CH554844A/en not_active IP Right Cessation
-
1969
- 1969-08-04 SE SE6910878A patent/SE378242B/xx unknown
- 1969-08-04 IL IL32767A patent/IL32767A/en unknown
- 1969-08-11 IE IE1125/69A patent/IE33519B1/en unknown
- 1969-08-13 CS CS5600A patent/CS162689B2/cs unknown
- 1969-08-13 DE DE1966821A patent/DE1966821C3/en not_active Expired
- 1969-08-13 NL NL6912320A patent/NL6912320A/xx unknown
- 1969-08-13 BE BE737420D patent/BE737420A/xx unknown
- 1969-08-13 DE DE1941284A patent/DE1941284C3/en not_active Expired
- 1969-08-14 GB GB1250279D patent/GB1250279A/en not_active Expired
- 1969-08-14 DK DK436569AA patent/DK126776B/en unknown
- 1969-08-14 AT AT783669A patent/AT299158B/en not_active IP Right Cessation
- 1969-08-14 AT AT534671A patent/AT299160B/en not_active IP Right Cessation
- 1969-08-14 FR FR696928006A patent/FR2015792B1/fr not_active Expired
- 1969-08-14 ES ES370500A patent/ES370500A1/en not_active Expired
- 1969-08-15 JP JP44064663A patent/JPS5114501B1/ja active Pending
- 1969-08-15 CA CA059,620A patent/CA958418A/en not_active Expired
-
1971
- 1971-09-09 FR FR7132582A patent/FR2104722B1/fr not_active Expired
-
1973
- 1973-12-30 MY MY18/73A patent/MY7300018A/en unknown
Also Published As
Publication number | Publication date |
---|---|
CH554844A (en) | 1974-10-15 |
GB1250279A (en) | 1971-10-20 |
IL32767A0 (en) | 1969-11-12 |
AT299160B (en) | 1972-06-12 |
DE1941284A1 (en) | 1970-02-19 |
DE1941284B2 (en) | 1974-05-30 |
FR2015792B1 (en) | 1973-08-10 |
AT299158B (en) | 1972-06-12 |
SE378242B (en) | 1975-08-25 |
BE737420A (en) | 1970-02-13 |
NL6912320A (en) | 1970-02-18 |
DK126776B (en) | 1973-08-20 |
JPS5114501B1 (en) | 1976-05-10 |
DE1941284C3 (en) | 1975-01-30 |
ES370500A1 (en) | 1971-04-16 |
CS162689B2 (en) | 1975-07-15 |
FR2104722A1 (en) | 1972-04-21 |
IE33519L (en) | 1970-02-16 |
DE1966821A1 (en) | 1974-07-11 |
DE1966821C3 (en) | 1978-11-23 |
MY7300018A (en) | 1973-12-31 |
IE33519B1 (en) | 1974-07-24 |
FR2015792A1 (en) | 1970-04-30 |
FR2104722B1 (en) | 1974-03-22 |
DE1966821B2 (en) | 1978-03-16 |
CA958418A (en) | 1974-11-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4012444A (en) | 5-[1-Hydroxy-2-(1-methyl-3-phenylpropyl)aminoethyl] salicylamide and physiologically acceptable acid addition salts thereof | |
RU2001614C1 (en) | R(+)-n-propargyl-1-aminoindan and its pharmaceutically acceptable acid-additive salts, and pharmaceutical composition showing inhibitory activity relative to b-form of enzyme monoamineoxidase | |
JPH06102623B2 (en) | Central nervous system stimulant | |
IE45300B1 (en) | N-amionalkyl-heterocycles,methods for their preparation and compositions containing them | |
US4459301A (en) | Method of treating cardiac disorders using bispidine derivatives | |
IL36237A (en) | Substituted benzylimidazolidinones,their preparation and pharmaceutical compositions containing them | |
WO2006005112A1 (en) | Process for the synthesis of hydromorphone | |
EA021440B1 (en) | Process for the manufacture of a pharmaceutically active agent | |
JPS5929190B2 (en) | Sulfonamide compounds | |
US3557292A (en) | Compositions and methods for treating parkinson's disease with combinations of l-3,4-dihydroxyphenylalanine and a hydrazine | |
IL32767A (en) | A hydrazide and its acid addition salts | |
CN111454271B (en) | Sodium salt and crystal form of pyrrolidine carboxylic acid compound and preparation method thereof | |
NO742361L (en) | ||
US4683245A (en) | Laevorotatory antipode of moprolol as an antihypertensive | |
FR2540870A1 (en) | NOVEL DERIVATIVES OF N-IMINOPYRIDINIUM BETA, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS | |
US4279914A (en) | Thrombocyte aggregation inhibiting composition and methods | |
FR2496663A1 (en) | NOVEL NAPHTHYRIDINE-1,8 DERIVATIVES USEFULLY AS ANTIBACTERIAL MEDICINES | |
US3701829A (en) | Treatment of parkinson's disease | |
US4066755A (en) | Phenylaminoethanol derivatives for treating hypertension | |
US2946796A (en) | Salts of ergot alkaloids | |
US3976782A (en) | 3-(2,5-Dihydroxyphenyl)-alanine as a cardiac stimulant | |
CA1207797A (en) | Substituted 2,5-diaminopentanes, their preparation and drugs containing these compounds | |
US3456059A (en) | N1-(2 - (p-hydroxyphenyl)ethyl)biguanide as a hypoglycemic agent and as a weight reducing agent | |
IL43008A (en) | Dibenzazecines and processes for the production thereof | |
JPS6028838B2 (en) | Method for producing nitrogen-containing polycyclic compound |