CA1152100A - Derivatives of 3-aminopropanesulfonic acid having a reinforced activity on membrane - Google Patents
Derivatives of 3-aminopropanesulfonic acid having a reinforced activity on membraneInfo
- Publication number
- CA1152100A CA1152100A CA000352613A CA352613A CA1152100A CA 1152100 A CA1152100 A CA 1152100A CA 000352613 A CA000352613 A CA 000352613A CA 352613 A CA352613 A CA 352613A CA 1152100 A CA1152100 A CA 1152100A
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- Canada
- Prior art keywords
- acetyl
- whenever prepared
- homotaurinate
- chemical equivalent
- obvious chemical
- 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.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
- C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
- C07C309/15—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton the nitrogen atom of at least one of the amino groups being part of any of the groups, X being a hetero atom, Y being any atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
PATENT APPLICATION
In the name of : LES LABORATOIRES MERAM
Novel derivatives of 3-aminopropanesulfonic acid having a reinforced activity on membrane ABSTRACT
The present invention relates to novel salts of sodium, potassium, lithium, calcium, magnesium, zinc of N-acetyl-homotaurine having a reinforced activity on membrane, to the process for preparation thereof and to application thereof as neurotropic, vasculotropic and anti-asthenic medicaments.
In the name of : LES LABORATOIRES MERAM
Novel derivatives of 3-aminopropanesulfonic acid having a reinforced activity on membrane ABSTRACT
The present invention relates to novel salts of sodium, potassium, lithium, calcium, magnesium, zinc of N-acetyl-homotaurine having a reinforced activity on membrane, to the process for preparation thereof and to application thereof as neurotropic, vasculotropic and anti-asthenic medicaments.
Description
z~
NOVEL DERIVATIVES OF 3-~INOPROPANESULFONIC
ACID HAVING A REINFORCED ACTIVITY ON ~MBRANE
3-aminopropanesulfonic acid (3-~.PS or homotaurine) possesses, like its lower homologue 2-amiroethanesulfonic acid (or taurine), biological, and particularly neuromuscular and vasculo-metabolic properties These seem to depend on 5 its properties of membrane stabilisation which have been -demonstrated for the 3-APS, whilst their importance was already known for taurine.
This analogy between the two homologues (3-APS and taurine) cannot conceal the profound differences existing bet-10 ween these two molecules. Taurine is a physiological molecule -present and active in the organis~n, whilst 3-APS does not exist therein spontaneously. Moreover, the biological properties of the two molecules are known to be ~lualitatively and ~ antita-ti vely diff e rent.
. ' - ' ~ .
If the polarity of the molecule of 3-APS is modifled, b~
blocking the pr~mary amine by acetylation, stable and well-defined salts may be obtained.
- It has surprizingly been found that the novel salts of 3-acetylamlnopropanesulfonic acid according to the invèntion present ZO a relnforced stabilising activity on membrane.
.
The invention therefore~ relates to derivatives of 3-~PS
(or homotaurine~of forrnula: -~CH3C:ONH~(CH ) -SO ~ M
in which M represents an atom of alkali n~etal, i. e~ sodium, - 25 potassiu~n or lithium, and, in these cases, n is equal to 1, oran atom of magnesiu~n, calcium or æinc, ancl, in thececases~n is equal to 2, and to the application thereof as medicaments.
: . .
The invention also relates to a process for preparing the derivatives of formula I, wherein th~ base M(OH)n and the 3-APS
30 acid aF~ dissolved in water, posslbiy in the presenc`e of acetic acid, ... . . . . . .
~'. "
. ' - .
~7J~
acetic anhydride is then introduced into the solution obtained, so as to maintain a temperature of 30 to 40C and the mixture is left to react at this temperature for about 1 hour. The solution obtained is concentrated to dryness, the residue is redissolved in distilled 5: water and the solution concentrated to dryness again in order to obtain the product in the form of a crystalline powder.
The following examples are intended to illustrate the pro- .-cess for preparing the compounds according to the invention.
EX~MPLE I - P~eparation of sodium N-acetvlhomotaurinate . lQ (3-acetyiaminopropanesulfonate of sodium) - CH3CO - NH - C~12 - CHz - C:H2 - S03Na . In a 4 litre flask provided with stirring means, a bromine funnel and a thermometer, 1 216 g of 17. 5% sodium hydroxide solution and 7~0 g of homotaurine are added.
, - 15 After complete dissolution, at a temperature of between 25 and 40C, 630 g of acetic anhydride are added so as not to exceed a temperature of betweèn 3a and 40C. The mixture is then mair~tained at this temperature by heatlng. for at least 1 hour.
. . The solution is t~en concentrated in vacuo., the residue is
NOVEL DERIVATIVES OF 3-~INOPROPANESULFONIC
ACID HAVING A REINFORCED ACTIVITY ON ~MBRANE
3-aminopropanesulfonic acid (3-~.PS or homotaurine) possesses, like its lower homologue 2-amiroethanesulfonic acid (or taurine), biological, and particularly neuromuscular and vasculo-metabolic properties These seem to depend on 5 its properties of membrane stabilisation which have been -demonstrated for the 3-APS, whilst their importance was already known for taurine.
This analogy between the two homologues (3-APS and taurine) cannot conceal the profound differences existing bet-10 ween these two molecules. Taurine is a physiological molecule -present and active in the organis~n, whilst 3-APS does not exist therein spontaneously. Moreover, the biological properties of the two molecules are known to be ~lualitatively and ~ antita-ti vely diff e rent.
. ' - ' ~ .
If the polarity of the molecule of 3-APS is modifled, b~
blocking the pr~mary amine by acetylation, stable and well-defined salts may be obtained.
- It has surprizingly been found that the novel salts of 3-acetylamlnopropanesulfonic acid according to the invèntion present ZO a relnforced stabilising activity on membrane.
.
The invention therefore~ relates to derivatives of 3-~PS
(or homotaurine~of forrnula: -~CH3C:ONH~(CH ) -SO ~ M
in which M represents an atom of alkali n~etal, i. e~ sodium, - 25 potassiu~n or lithium, and, in these cases, n is equal to 1, oran atom of magnesiu~n, calcium or æinc, ancl, in thececases~n is equal to 2, and to the application thereof as medicaments.
: . .
The invention also relates to a process for preparing the derivatives of formula I, wherein th~ base M(OH)n and the 3-APS
30 acid aF~ dissolved in water, posslbiy in the presenc`e of acetic acid, ... . . . . . .
~'. "
. ' - .
~7J~
acetic anhydride is then introduced into the solution obtained, so as to maintain a temperature of 30 to 40C and the mixture is left to react at this temperature for about 1 hour. The solution obtained is concentrated to dryness, the residue is redissolved in distilled 5: water and the solution concentrated to dryness again in order to obtain the product in the form of a crystalline powder.
The following examples are intended to illustrate the pro- .-cess for preparing the compounds according to the invention.
EX~MPLE I - P~eparation of sodium N-acetvlhomotaurinate . lQ (3-acetyiaminopropanesulfonate of sodium) - CH3CO - NH - C~12 - CHz - C:H2 - S03Na . In a 4 litre flask provided with stirring means, a bromine funnel and a thermometer, 1 216 g of 17. 5% sodium hydroxide solution and 7~0 g of homotaurine are added.
, - 15 After complete dissolution, at a temperature of between 25 and 40C, 630 g of acetic anhydride are added so as not to exceed a temperature of betweèn 3a and 40C. The mixture is then mair~tained at this temperature by heatlng. for at least 1 hour.
. . The solution is t~en concentrated in vacuo., the residue is
2:0 redissolved in ~ 5 1 of distilled water and the mixture is ~oncen-trated again~ The residua is then ctissolved in 1~ 61 of distilled water~
filtered~ ther~ concentrated almos~ completely. : -.
I:~rying is terminated in an o~Fen in v:acuQ. ~ c~lourless erystalline pc~wder is obtainaa, Yield ~2~ P. 1~0-150C ~ Gontent of water ~, 4~Q
~na1ysis % calculate~ ~ found . Nitr~gen 6, 89 6, 80 5Odium 11 33 .11, o6 , ~ , , ~ ' . .
' ,.... . .
~, EXA M PLE 2 - Preparation of potassium N-acetylhomotaurinate (3-acetylaminopropanesulfonate of potassium) CH3C0 - ~H ~ CH2 ~ CH ~ CH2 ~ S0 K
In the same apparatus as for the preceding salt, 1 700 g of 15. 4% potassium hydroxide solution and 650 g of homotaurine are introduced.
~fter dissolution, 552 g of acetic anhydride are introduced, the temperature remaining between 30 and 40C. This ternperature is then maintained for 1 hour. The solution obtained is concentrated in vacuo, the residue is redissolved in 2.1501 of distilled water.
, Aiter a-new concentration, the product is redissolved in 1. 51 of distllled water, filtered, then concentrated almost compietely.
Drying is terminated in an o~,en in vacuo. A colourless crystalline powder is obtained.
15 Yield: 96%, m. p. 205-207C ~ ater content: 1. 6%
Analysis % calculated % found Nitrogen 6. 38 6. 27 Potàssium 17, 84 17. 39 EXAlvlPLE 3 - Preparation of lithium N~acetylhomotaurinate . .
20 cH3c( ~ - NH - CH2 - CH2 - CHz - 503Li 1 242 g of 10. 5% lithiom hydroxide solution and 750 g of homotaurine are introduced into the same apparatus as before.
Under the same conditions as for the preceding salts, 630 g of acetic anhydride are added and~ the treatment i9 carried out 25 according to the modus op~randi indicatqd harelnabQve. ~ colour-less crystalline powder is obtained~
Yield: 95%, m. p~ 29~-2~6~C - ~Tater conten~: 0 6%
Analysis % calculated % ~ound Nitro~en 7~.~48 7.39 . . 30 Lithium 3,7 . 3~56 ~ .
' ' , ' ' ' . ' ~ ''' ' ' , .
.
oo EXAMPLE 4 - Preparation of calcium N-acetylhomotaurinate (CH3C0 - NH - CH2 - CH2 - CH2 - SO3)2Ca 200 ml of distilled water, 19. 7 g of calcium hydroxide, 32 g of acetic acid and 75 g of homotaurine are introduced into a 3-necked 5 1 litre flask .
Stirring is effected at a temperature of between 25 and 40C until dissolution, then 63 g of acetic anhydride are introduced, so as not to exceed a temperature of between 30~and 40C. This temperature is then maintained for 1 hour. The solution obtained is treated as in 10 the preceding preparations. ~A colourless crystalline powder is obtained "
Yield: 90%, m. p. about 270C (not clear) - ~Fater content 3. 6%
Analysis % calculated <7rQ found Nitrogen 7 . 6. 8 Cal ciurrl10 9 7 EXAMPLE 5 - Preparation of ma~nesium N-acetylhomotaurinate (CH CO - NH - CH2 - CH2 - CH2 - S03)Mg 45 ml of distilled-water, 2. 74 g of pure magnesium oxide, 8. Z g of acetic acid and 19 g of homotaurinè are introduced into 20 a three-neclced 250 ml flask.
~: .
Stirring is effected at a temperature of between 25 and 40C
until dissolution, than 15 g of acetic anhydride are introduced sa as to obtain a temperature of between:30 and 40C. This temperature - is then maintained for on~ hour. The solution obtalned is treated as 25 in the preceding preparations, At ~he end of concentration, a product of syrupy consistenc~
is obtained. After drying in vacuo, the amo~rphous product is ground and dried again. - A colourless powder i9 obtained.
Yield 90%
30 ~nalysis ~0 calculated % found Nitrogen 7, 28 7. 06 Magnesium6. 32 6.1~
.. . .
. ~ ' ~5?~1~)0 EX~MPLE 6 - Preparat_n of zinc N-_etvlhomotaurinate (CH3CO - NH - CH2 - CHz - CH2 - SO3)2Zn This salt is prepared in the same manner as the preceding ones; a product is obtained whose analysis is as follo~,~s 5 Analysis 'lo calculated % found Nitrogen 6. 6 5. 82 Zinc 15. 3 L4. 48 i~ny other salt of metals or organic bases such as papaverines, ethanolamine, vincamine, etc, . may also be prepared by the same 10 process Pharmacol~ }~ perties The toxicity of the derivatives according to the invention have been studied in the male mouse. Table I hereinbelow gives the LD
by intraperitoneal route e~pressed in g/k~ of substance and in 15 mg of ion/kg. The stabllising action o~ t4e compounds of the invention has been studied on the erythrocyte membrane in vitro by the con-ventional method of J. H. Brown et coll., Proc Soc. Exp. Biol. ~ed.
(1967)125, 837 to 842; and W. Mikikits et coll, Nature ~1970) 225, March 21, 1150-1151. This method makes it possible to demonstrate 20 ` a stabilising effect on the red cell membrane of the rabbit, by studying the rate of haemolysis, during incubation in hypotonic medium (1~ mh~ phosphate buffer - pH 7. 4 - l~aCl 5. 5 g~lj and with heat ~53C). The products to be studied are added to the in-cubation medium at different concentrations`~ The rate of haemoly3is 25 is compared w1th that of a control. The ED!;o is thus deterrnined and the values obtained are given in Ta~le II hereinbelow in mM~l This Table shows that the novel deriva~ives according to the inven-tion present a stabilisation activ1ty on the membrane greater than that of 3-APS (homotaurine). .Vhilst the ~D50`of homotaurine is 30 15 mM/1, that of the compounds according to the invention varies from 1 to 10; it is therefore always le~s than that of homotaurine ~ .
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1~ 5~0~
and up to 15 times less. It is obvious that this pharrnacological property of all the derivatives accordi'ng to the invention is trans-lated by properties cornmon thereto; however, according to the nature of the cation, the compounds.present singularities which 5 enable certain salts to be used in certain applications rather than others .
.
Thus, in the rat, whilst homotaurine by the intraperitoneal route does not modify the rectal temperature, the derivatives according to the invention all cause a hypothermia. However, the 10 salts of bivalent cations are more active than those of rnonovalent cation's and that of calcium more ~active than that of magnesium.
This same ranking is found in the antagonism e~erted by the com- -pounds according to the invention on the motive excitation obtalned in the mouse by ethanol. ~ - -, The antagonism of the'acetylhomotaurinates according to the . invention vls-~-vis the hyp'ermotility caused b'y ethanol has been studled by the test of Cott-Carlsson Engel Lindqvi3t, Naunyn-Schmiedeberg's Archlves of Pharmacology 295, 203-209 tl976~;
Female mice, distributed in batches of 9,' receive the products to 20 be tested per 08 one hour before the lntraperitoneal injection of a solution of ethanol.' The rnotility of the mlce placed in the acti-meter ls recorded immedlately after thls injection, every 5 minutes, for 6Q minutes. The percentage of v:?riation a~ the motility af the mi c e- treal:ed with ethanol ~ith r~sp~et to the controls rec eiving 25 water is determined, and of m}ce treated~ with the praàuct to be tested and wit h ethanol with respect to mice receiving only , ethanol.
: ,, . : . . ' .
The products accordl~g to the invention have been studied, in this test, ~t the follawing doses~ 8Q, 100, 200, 4ûO and 80Q mg~/kg 30 per os. The results are as follows: The æodiurn acetylhomotaurinate .
,. . .
.. . . .
.. . ~ ... .
- - . ' -.
.
~:~5;2~0~
~proves to be the least active (at a dose of 400 mg/kg slight antagonism which appears at the 50th minute of observation). .
The calcium acetylhomotaurinate maniiests, at a dose of 200 and 400 mg /kg, a significant antagonism on the hypermotility 5 by ethanol; this effect is confirmed at' the dose of 800 mg/kg but does not appear to be superior to that recorded at 400 mg.
At the doses of 200 and 40~) mg/kg, the antagonistic effect of magnesium acetylhomotaurinate i.s slightly less than that of the calcium salt.
. 10 ' It should be noted that, at the same doses, the corresponding salts of the acetyltaurine present only little or no antagonistic effect in this test of hypermotility by ethanol.
The results are summarized In TabIe III herein'. elow.
' The compounds according to the invention also present an 15 anti-convulsiv.ant action on the convulsions caused in.the mouse by pentetrazol: After administration of pentetrazol, the time : of appearance of the convulsions and the time of appearance of death is~mea~ured, in the animals which previously receivedj by - : , the intraperitoneal route, the product to be tested! comparatively 20 to controls receiving only' pentetrazol.
The results are as foilows ~t the respective doses of ~9~ mL~
and 315 mglkg (i. p. ), the. sodium and. potassium acetylhomotaurina~es increase, without reaching the.level of significance, the time oi.
appearance of the convulsions and that oi death However, mag- -25 nesium acetylhomotaurinate'is ac~tive at 400 mg/kg (i. p. J (significant on the time of appearance of death) and at 800 mg;/kg (i. p. )(significant on the tirne of appearance of conv_ulsions~. . The calcium acetyl-homotaurinate manifests, at 400 and 800 mg/kg. (i. p. ) a significant ~:~ antagonism (xx) on the time of appearance of death; the effect on the ~:: 30 time of appearance of the convulsio'ns is significant only at the dose ... . .
.. , ~ . . ., ~ , . .
, ., . ; . ; , . ~ ~ ., : .
- . ..
.
- ~ . . .
'' . , ' ' :
' ' ' . .':: ~ : ' . ' ' ' ' ~L~5;2100 of 800 mgjkg; it is very signiiicant (xxx) at the dose of 100U mg/kg In summary, the anti-convulsivant activity of Ca acetylhomo-taurinate is, like the sedative activity, greater than that of Mg acetylhomotaurinate, It should be noted that, measured by the same test, the corresponding activity of the salts of acetyltaurine is very clearly less, at the same doses, than that of the corresponding acetyl-homotaurinates; Ca acetyltaurinate acting significantly (x) on the time of app~ arance of death only at the dose of 1000 mg/kg (i. p. ) and Mg acetyltaurinate acting significantly (xxJ on the times of appearance of the conv_ulsions and of death only at the dose of 100(~ mg/kg likewise.
, . The magnesium and lithium salts are distinguished ln that they significantly reduce the to:xicity of their cation. The LD50 1.5 by the intraperitoneal route in the mouse is, expressed in Mgt+, 94 mg for.the magnesium chloride and, expressed in Li~, 88 mg for the lithium carbonate (reference salts~. This LDSo is .
significantly increased for the compounds according to the inven-tion: magnesium acetylhomotaurinate: 161 mg and lithium acetyl-homotaurinate:l57 mg.
On the othèr hand, the potassium salt proves in the rat to be the most active in the tes~t of thè muscle fatigued by application of . lactic acid. Th~ sodium salt by the oral route comes at the top of the serie~ for.the potentialization~in the ms~use of narcosis by 2~ ethanol. It is furttermore suitable for the manufactuxe of aqueous golution~ . . ` .
'~
~: . Therapeutic application The various compounds according to the invention may be . -. ~ administered by the general and local routes and in aIl forms~
~ tablets, cachets, capsules, suspensions,. solutions, syrups- For ., ' ' ' ' ' ' .
-, . .
,.,. " , - -, - , ~ ~' . - - -.
:
~15~ 0 the local route, particular emphasis should be given to eye washes in aqueous solution, nose drops, ointments and aerosols.
The therapeutic indications may be slightly different accor-ding to the properties of the cation.
, The calcium salt may be used as neurotropic agent; the magnesium salt as vasculotropic agent; the potassium salt as antiasthenic agent; the llthium salt may be used in for bipol~r patiPnts and the sodium salt in local treatments; the zinc salt may be used in dermatology.
By way of example, posology is at the usuai doses of lg/day per 05 or by the parenteral route, For example, the nnagnesium acetylhomotaurinate has been used in the form of sectile cachets of 0. 50 g at the average usual dose of 1 g per ~4 hours, which rnay be reduced by half or, on the 15 contrary, widely exceeded up to 5 g~day. For parenteral route.
ampoules of aqueous solution of acetylhomotaurinate may be used, for example of magnesium at 1 g per 10 ml, in slow intravenous route, due to the irnpression of heat that ~hey give, or, better, in perfusions, intramuscular or sub-cutaneous. I`he doses vary from one intra-2Q muscular ampoule per day to a maximum of ten ampoules in slow perfusion~ nd~r hospitaL condiSions.
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TABLE I
Toxi city LD50 (male mouse, i. p, )g/kgmg cation/kg Sodium acetylhomotaurinate greater than 5 g Potassium acetylhomotaurinate . 4,12 g - 733 mg Lithium acetylhomotaurinate 4. 26 g 157 mg Calcium acetylhomotaurinate: 1, 87 g 186 mg Magnesium acetylhomotaurinate 2. 57 g 161 mg .
( Calcium acetyltaurinate: LD50 by oral route = 13. 09 g/kg) ' TA B L E~ II .
Stabilising efect on the erythrocyte membrane of the r~bbit : ED50, expressed in mM/l Homotaurine . 15 .
Sodium asetylhomotaurinate 5 Potassium acetylhomotaurinate .5 Lithium acetylhornotaurinate lQ
Magneslum acetylhomotaurin~te 10 Calcium acetylho~otaurinate , . ' ' ' ' , ' ' - . . , ' ' - ' ' , , ' ' ' ' , .
.
. ,j , . . ..
, ~' :
~5~00 .
TAB LE III
Antagonism of the hypermotility by ethanol Products Doses Results Significance (per os) _ Calcium acetyl- 80 mg 0 homot'aurinate 100 mg antagonism xxx, 200 mg antagonism xx 400 mg . antagonism , x 800 mg antagonism, xx (shorterj .
Magnesium acetyl- 80 mg antagonism x ' homotaurinate 100 m~g antagonism ' not' significant 200 mg 'antagoni 9m X
' 400 mg antagonism ' x Sodium acetyl- ~00 mg slight anta,- not significant ' - homotaurinate ,,~onism Magnesium acetyl- lQ0 mg antagonism not significant . taurinate 200 mg ~a~tagonism . ' not significant 4 00 O 1 . -. : ' Calcium acetyl- ~ 8Q mg ~ ::- 0 tauri2~ate . ~oo ~g ~ ~ Q
8Q0 mg :~ antagonism ~ 'x to xx according - ' . . t o the time Sodium ac~tyl- 40~ mg ~ O .
taurinate, : . ~ . ~ ~ - ` : -- . - . :
~: S''l ' ' . : - ' .
.
~ .,~., . ~ -. ,~
filtered~ ther~ concentrated almos~ completely. : -.
I:~rying is terminated in an o~Fen in v:acuQ. ~ c~lourless erystalline pc~wder is obtainaa, Yield ~2~ P. 1~0-150C ~ Gontent of water ~, 4~Q
~na1ysis % calculate~ ~ found . Nitr~gen 6, 89 6, 80 5Odium 11 33 .11, o6 , ~ , , ~ ' . .
' ,.... . .
~, EXA M PLE 2 - Preparation of potassium N-acetylhomotaurinate (3-acetylaminopropanesulfonate of potassium) CH3C0 - ~H ~ CH2 ~ CH ~ CH2 ~ S0 K
In the same apparatus as for the preceding salt, 1 700 g of 15. 4% potassium hydroxide solution and 650 g of homotaurine are introduced.
~fter dissolution, 552 g of acetic anhydride are introduced, the temperature remaining between 30 and 40C. This ternperature is then maintained for 1 hour. The solution obtained is concentrated in vacuo, the residue is redissolved in 2.1501 of distilled water.
, Aiter a-new concentration, the product is redissolved in 1. 51 of distllled water, filtered, then concentrated almost compietely.
Drying is terminated in an o~,en in vacuo. A colourless crystalline powder is obtained.
15 Yield: 96%, m. p. 205-207C ~ ater content: 1. 6%
Analysis % calculated % found Nitrogen 6. 38 6. 27 Potàssium 17, 84 17. 39 EXAlvlPLE 3 - Preparation of lithium N~acetylhomotaurinate . .
20 cH3c( ~ - NH - CH2 - CH2 - CHz - 503Li 1 242 g of 10. 5% lithiom hydroxide solution and 750 g of homotaurine are introduced into the same apparatus as before.
Under the same conditions as for the preceding salts, 630 g of acetic anhydride are added and~ the treatment i9 carried out 25 according to the modus op~randi indicatqd harelnabQve. ~ colour-less crystalline powder is obtained~
Yield: 95%, m. p~ 29~-2~6~C - ~Tater conten~: 0 6%
Analysis % calculated % ~ound Nitro~en 7~.~48 7.39 . . 30 Lithium 3,7 . 3~56 ~ .
' ' , ' ' ' . ' ~ ''' ' ' , .
.
oo EXAMPLE 4 - Preparation of calcium N-acetylhomotaurinate (CH3C0 - NH - CH2 - CH2 - CH2 - SO3)2Ca 200 ml of distilled water, 19. 7 g of calcium hydroxide, 32 g of acetic acid and 75 g of homotaurine are introduced into a 3-necked 5 1 litre flask .
Stirring is effected at a temperature of between 25 and 40C until dissolution, then 63 g of acetic anhydride are introduced, so as not to exceed a temperature of between 30~and 40C. This temperature is then maintained for 1 hour. The solution obtained is treated as in 10 the preceding preparations. ~A colourless crystalline powder is obtained "
Yield: 90%, m. p. about 270C (not clear) - ~Fater content 3. 6%
Analysis % calculated <7rQ found Nitrogen 7 . 6. 8 Cal ciurrl10 9 7 EXAMPLE 5 - Preparation of ma~nesium N-acetylhomotaurinate (CH CO - NH - CH2 - CH2 - CH2 - S03)Mg 45 ml of distilled-water, 2. 74 g of pure magnesium oxide, 8. Z g of acetic acid and 19 g of homotaurinè are introduced into 20 a three-neclced 250 ml flask.
~: .
Stirring is effected at a temperature of between 25 and 40C
until dissolution, than 15 g of acetic anhydride are introduced sa as to obtain a temperature of between:30 and 40C. This temperature - is then maintained for on~ hour. The solution obtalned is treated as 25 in the preceding preparations, At ~he end of concentration, a product of syrupy consistenc~
is obtained. After drying in vacuo, the amo~rphous product is ground and dried again. - A colourless powder i9 obtained.
Yield 90%
30 ~nalysis ~0 calculated % found Nitrogen 7, 28 7. 06 Magnesium6. 32 6.1~
.. . .
. ~ ' ~5?~1~)0 EX~MPLE 6 - Preparat_n of zinc N-_etvlhomotaurinate (CH3CO - NH - CH2 - CHz - CH2 - SO3)2Zn This salt is prepared in the same manner as the preceding ones; a product is obtained whose analysis is as follo~,~s 5 Analysis 'lo calculated % found Nitrogen 6. 6 5. 82 Zinc 15. 3 L4. 48 i~ny other salt of metals or organic bases such as papaverines, ethanolamine, vincamine, etc, . may also be prepared by the same 10 process Pharmacol~ }~ perties The toxicity of the derivatives according to the invention have been studied in the male mouse. Table I hereinbelow gives the LD
by intraperitoneal route e~pressed in g/k~ of substance and in 15 mg of ion/kg. The stabllising action o~ t4e compounds of the invention has been studied on the erythrocyte membrane in vitro by the con-ventional method of J. H. Brown et coll., Proc Soc. Exp. Biol. ~ed.
(1967)125, 837 to 842; and W. Mikikits et coll, Nature ~1970) 225, March 21, 1150-1151. This method makes it possible to demonstrate 20 ` a stabilising effect on the red cell membrane of the rabbit, by studying the rate of haemolysis, during incubation in hypotonic medium (1~ mh~ phosphate buffer - pH 7. 4 - l~aCl 5. 5 g~lj and with heat ~53C). The products to be studied are added to the in-cubation medium at different concentrations`~ The rate of haemoly3is 25 is compared w1th that of a control. The ED!;o is thus deterrnined and the values obtained are given in Ta~le II hereinbelow in mM~l This Table shows that the novel deriva~ives according to the inven-tion present a stabilisation activ1ty on the membrane greater than that of 3-APS (homotaurine). .Vhilst the ~D50`of homotaurine is 30 15 mM/1, that of the compounds according to the invention varies from 1 to 10; it is therefore always le~s than that of homotaurine ~ .
: .
-, ~ - . : -. . .
. ~
,. .: , . ,- :
. ~
, ' ' ' ' . ` ' .
1~ 5~0~
and up to 15 times less. It is obvious that this pharrnacological property of all the derivatives accordi'ng to the invention is trans-lated by properties cornmon thereto; however, according to the nature of the cation, the compounds.present singularities which 5 enable certain salts to be used in certain applications rather than others .
.
Thus, in the rat, whilst homotaurine by the intraperitoneal route does not modify the rectal temperature, the derivatives according to the invention all cause a hypothermia. However, the 10 salts of bivalent cations are more active than those of rnonovalent cation's and that of calcium more ~active than that of magnesium.
This same ranking is found in the antagonism e~erted by the com- -pounds according to the invention on the motive excitation obtalned in the mouse by ethanol. ~ - -, The antagonism of the'acetylhomotaurinates according to the . invention vls-~-vis the hyp'ermotility caused b'y ethanol has been studled by the test of Cott-Carlsson Engel Lindqvi3t, Naunyn-Schmiedeberg's Archlves of Pharmacology 295, 203-209 tl976~;
Female mice, distributed in batches of 9,' receive the products to 20 be tested per 08 one hour before the lntraperitoneal injection of a solution of ethanol.' The rnotility of the mlce placed in the acti-meter ls recorded immedlately after thls injection, every 5 minutes, for 6Q minutes. The percentage of v:?riation a~ the motility af the mi c e- treal:ed with ethanol ~ith r~sp~et to the controls rec eiving 25 water is determined, and of m}ce treated~ with the praàuct to be tested and wit h ethanol with respect to mice receiving only , ethanol.
: ,, . : . . ' .
The products accordl~g to the invention have been studied, in this test, ~t the follawing doses~ 8Q, 100, 200, 4ûO and 80Q mg~/kg 30 per os. The results are as follows: The æodiurn acetylhomotaurinate .
,. . .
.. . . .
.. . ~ ... .
- - . ' -.
.
~:~5;2~0~
~proves to be the least active (at a dose of 400 mg/kg slight antagonism which appears at the 50th minute of observation). .
The calcium acetylhomotaurinate maniiests, at a dose of 200 and 400 mg /kg, a significant antagonism on the hypermotility 5 by ethanol; this effect is confirmed at' the dose of 800 mg/kg but does not appear to be superior to that recorded at 400 mg.
At the doses of 200 and 40~) mg/kg, the antagonistic effect of magnesium acetylhomotaurinate i.s slightly less than that of the calcium salt.
. 10 ' It should be noted that, at the same doses, the corresponding salts of the acetyltaurine present only little or no antagonistic effect in this test of hypermotility by ethanol.
The results are summarized In TabIe III herein'. elow.
' The compounds according to the invention also present an 15 anti-convulsiv.ant action on the convulsions caused in.the mouse by pentetrazol: After administration of pentetrazol, the time : of appearance of the convulsions and the time of appearance of death is~mea~ured, in the animals which previously receivedj by - : , the intraperitoneal route, the product to be tested! comparatively 20 to controls receiving only' pentetrazol.
The results are as foilows ~t the respective doses of ~9~ mL~
and 315 mglkg (i. p. ), the. sodium and. potassium acetylhomotaurina~es increase, without reaching the.level of significance, the time oi.
appearance of the convulsions and that oi death However, mag- -25 nesium acetylhomotaurinate'is ac~tive at 400 mg/kg (i. p. J (significant on the time of appearance of death) and at 800 mg;/kg (i. p. )(significant on the tirne of appearance of conv_ulsions~. . The calcium acetyl-homotaurinate manifests, at 400 and 800 mg/kg. (i. p. ) a significant ~:~ antagonism (xx) on the time of appearance of death; the effect on the ~:: 30 time of appearance of the convulsio'ns is significant only at the dose ... . .
.. , ~ . . ., ~ , . .
, ., . ; . ; , . ~ ~ ., : .
- . ..
.
- ~ . . .
'' . , ' ' :
' ' ' . .':: ~ : ' . ' ' ' ' ~L~5;2100 of 800 mgjkg; it is very signiiicant (xxx) at the dose of 100U mg/kg In summary, the anti-convulsivant activity of Ca acetylhomo-taurinate is, like the sedative activity, greater than that of Mg acetylhomotaurinate, It should be noted that, measured by the same test, the corresponding activity of the salts of acetyltaurine is very clearly less, at the same doses, than that of the corresponding acetyl-homotaurinates; Ca acetyltaurinate acting significantly (x) on the time of app~ arance of death only at the dose of 1000 mg/kg (i. p. ) and Mg acetyltaurinate acting significantly (xxJ on the times of appearance of the conv_ulsions and of death only at the dose of 100(~ mg/kg likewise.
, . The magnesium and lithium salts are distinguished ln that they significantly reduce the to:xicity of their cation. The LD50 1.5 by the intraperitoneal route in the mouse is, expressed in Mgt+, 94 mg for.the magnesium chloride and, expressed in Li~, 88 mg for the lithium carbonate (reference salts~. This LDSo is .
significantly increased for the compounds according to the inven-tion: magnesium acetylhomotaurinate: 161 mg and lithium acetyl-homotaurinate:l57 mg.
On the othèr hand, the potassium salt proves in the rat to be the most active in the tes~t of thè muscle fatigued by application of . lactic acid. Th~ sodium salt by the oral route comes at the top of the serie~ for.the potentialization~in the ms~use of narcosis by 2~ ethanol. It is furttermore suitable for the manufactuxe of aqueous golution~ . . ` .
'~
~: . Therapeutic application The various compounds according to the invention may be . -. ~ administered by the general and local routes and in aIl forms~
~ tablets, cachets, capsules, suspensions,. solutions, syrups- For ., ' ' ' ' ' ' .
-, . .
,.,. " , - -, - , ~ ~' . - - -.
:
~15~ 0 the local route, particular emphasis should be given to eye washes in aqueous solution, nose drops, ointments and aerosols.
The therapeutic indications may be slightly different accor-ding to the properties of the cation.
, The calcium salt may be used as neurotropic agent; the magnesium salt as vasculotropic agent; the potassium salt as antiasthenic agent; the llthium salt may be used in for bipol~r patiPnts and the sodium salt in local treatments; the zinc salt may be used in dermatology.
By way of example, posology is at the usuai doses of lg/day per 05 or by the parenteral route, For example, the nnagnesium acetylhomotaurinate has been used in the form of sectile cachets of 0. 50 g at the average usual dose of 1 g per ~4 hours, which rnay be reduced by half or, on the 15 contrary, widely exceeded up to 5 g~day. For parenteral route.
ampoules of aqueous solution of acetylhomotaurinate may be used, for example of magnesium at 1 g per 10 ml, in slow intravenous route, due to the irnpression of heat that ~hey give, or, better, in perfusions, intramuscular or sub-cutaneous. I`he doses vary from one intra-2Q muscular ampoule per day to a maximum of ten ampoules in slow perfusion~ nd~r hospitaL condiSions.
. ' ' . :' ' ,, ' ' ' ' `
- .' ' ' ' .. ~ , '' ' '' ', ' .
.
.
~, . ~ . . . .
.. :
~5~
TABLE I
Toxi city LD50 (male mouse, i. p, )g/kgmg cation/kg Sodium acetylhomotaurinate greater than 5 g Potassium acetylhomotaurinate . 4,12 g - 733 mg Lithium acetylhomotaurinate 4. 26 g 157 mg Calcium acetylhomotaurinate: 1, 87 g 186 mg Magnesium acetylhomotaurinate 2. 57 g 161 mg .
( Calcium acetyltaurinate: LD50 by oral route = 13. 09 g/kg) ' TA B L E~ II .
Stabilising efect on the erythrocyte membrane of the r~bbit : ED50, expressed in mM/l Homotaurine . 15 .
Sodium asetylhomotaurinate 5 Potassium acetylhomotaurinate .5 Lithium acetylhornotaurinate lQ
Magneslum acetylhomotaurin~te 10 Calcium acetylho~otaurinate , . ' ' ' ' , ' ' - . . , ' ' - ' ' , , ' ' ' ' , .
.
. ,j , . . ..
, ~' :
~5~00 .
TAB LE III
Antagonism of the hypermotility by ethanol Products Doses Results Significance (per os) _ Calcium acetyl- 80 mg 0 homot'aurinate 100 mg antagonism xxx, 200 mg antagonism xx 400 mg . antagonism , x 800 mg antagonism, xx (shorterj .
Magnesium acetyl- 80 mg antagonism x ' homotaurinate 100 m~g antagonism ' not' significant 200 mg 'antagoni 9m X
' 400 mg antagonism ' x Sodium acetyl- ~00 mg slight anta,- not significant ' - homotaurinate ,,~onism Magnesium acetyl- lQ0 mg antagonism not significant . taurinate 200 mg ~a~tagonism . ' not significant 4 00 O 1 . -. : ' Calcium acetyl- ~ 8Q mg ~ ::- 0 tauri2~ate . ~oo ~g ~ ~ Q
8Q0 mg :~ antagonism ~ 'x to xx according - ' . . t o the time Sodium ac~tyl- 40~ mg ~ O .
taurinate, : . ~ . ~ ~ - ` : -- . - . :
~: S''l ' ' . : - ' .
.
~ .,~., . ~ -. ,~
Claims (14)
1. A method of forming a derivative of 3-aminopropane-sulfonic acid erprensented by the formula:
[CH3CONH-(CH2)3-SO3]nM
in which M represents an atom of a pharmaceutically acceptable monovalent or bivalent metal and n is 1 or 2, which comprises reacting 3-aminopropanesulfonic acid with a solution of a base represented by the formula M(OH)n, then introducing acetic anhydride into the solution so as to maintain the temperature between 30° and 40°C, maintaining the reaction temperature for about one hour, concentrating the resulting solution to dryness.
[CH3CONH-(CH2)3-SO3]nM
in which M represents an atom of a pharmaceutically acceptable monovalent or bivalent metal and n is 1 or 2, which comprises reacting 3-aminopropanesulfonic acid with a solution of a base represented by the formula M(OH)n, then introducing acetic anhydride into the solution so as to maintain the temperature between 30° and 40°C, maintaining the reaction temperature for about one hour, concentrating the resulting solution to dryness.
2. The method of claim 1 wherein the product is purified by dissolution in water and reconcentration to dryness.
3. The method of claim 1 wherein M represents sodium.
4. The method of claim 1 wherein M represents potassium.
5. The method of claim 1 wherein M represents lithium.
6. The method of claim 1 wherein M represents magnesium.
7. The method of claim 1 wherein M represents calcium.
8. A derivative of 3-aminopropanesulfonic acid represented by the formula:
[CH3CONH-(CE2)3-SO3]nM
in which M represents an atom of a pharmaceutically acceptable monovalent or bivalent metal and n is 1 or 2, whenever prepared by the method of claim 1 or by an obvious chemical equivalent thereof.
[CH3CONH-(CE2)3-SO3]nM
in which M represents an atom of a pharmaceutically acceptable monovalent or bivalent metal and n is 1 or 2, whenever prepared by the method of claim 1 or by an obvious chemical equivalent thereof.
9. A derivative of 3-aminopropanesulfonic acid represented by the formula:
[CH3CONH-(CH2)3-SO3]nM
in which M represents an atom of a pharmaceutically acceptable monovalent metal or of a bivalent metal and n is 1 or 2, whenever prepared by the method of claim 2 or by an obvious chemical equivalent thereof.
[CH3CONH-(CH2)3-SO3]nM
in which M represents an atom of a pharmaceutically acceptable monovalent metal or of a bivalent metal and n is 1 or 2, whenever prepared by the method of claim 2 or by an obvious chemical equivalent thereof.
10. Sodium N-acetyl-homotaurinate whenever prepared by the method of claim 3 or by an obvious chemical equivalent thereof.
11. Potassium N-acetyl-homotaurinate whenever prepared by the method of claim 4 or by an obvious chemical equivalent thereof.
12. Lithium N-acetyl-homotaurinate whenever prepared by the method of claim 5 or by an obvious chemical equivalent thereof.
13. Magnesium N-acetyl-homotaurinate whenever prepared by the method of claim 6 or by an obvious chemical equivalent thereof.
14. Calcium N-acetyl-homotaurinate whenever prepared by the method of claim 7.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7913207A FR2457281A1 (en) | 1979-05-23 | 1979-05-23 | NOVEL 3-AMINOPROPANESULFONIC ACID DERIVATIVES WITH ENHANCED MEMBRANE ACTIVITY |
| FR7913207 | 1979-05-23 |
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| Publication Number | Publication Date |
|---|---|
| CA1152100A true CA1152100A (en) | 1983-08-16 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000352613A Expired CA1152100A (en) | 1979-05-23 | 1980-05-23 | Derivatives of 3-aminopropanesulfonic acid having a reinforced activity on membrane |
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| JP (2) | JPS5625146A (en) |
| AT (1) | AT372371B (en) |
| AU (1) | AU535785B2 (en) |
| BE (1) | BE883468A (en) |
| CA (1) | CA1152100A (en) |
| CH (1) | CH647757A5 (en) |
| DE (2) | DE3019350A1 (en) |
| ES (1) | ES491787A0 (en) |
| FR (1) | FR2457281A1 (en) |
| GB (1) | GB2051789B (en) |
| GR (1) | GR68547B (en) |
| IT (1) | IT1130455B (en) |
| MA (1) | MA18855A1 (en) |
| MX (1) | MX9203363A (en) |
| NL (2) | NL191789C (en) |
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| HU193197B (en) * | 1984-02-03 | 1987-08-28 | Egyt Gyogyszervegyeszeti Gyar | Preparatives regulating the growth of plants containing as reagent derivatives of n-substituated amin-prophansulphonic acid and process for production of the reagent |
| JPH0725771B2 (en) * | 1992-06-18 | 1995-03-22 | 財団法人生産開発科学研究所 | 2-Aminoethanesulfonic acid zinc complex compound |
| US20040208875A1 (en) * | 1995-03-15 | 2004-10-21 | Queen's University At Kingston | Method for treating amyloidosis |
| AU703540B2 (en) * | 1996-03-26 | 1999-03-25 | Meddiss, Incorporated | Methods for inducing analgesia or anesthesia and treating or preventing ischemic injury of tissues in general |
| US6057373A (en) * | 1997-05-22 | 2000-05-02 | Synchroneuron, Llc | Methods of treating tardive dyskinesia and other movement disorders using NMDA receptor antagonists |
| US6391922B1 (en) | 1998-01-13 | 2002-05-21 | Synchroneuron, Llc | Treatment of posttraumatic stress disorder, obsessive-compulsive disorder and related neuropsychiatric disorders |
| US6294583B1 (en) * | 1998-01-13 | 2001-09-25 | Synchroneuron, Llc | Methods of treating tardive dyskinesia and other movement disorders |
| US5952389A (en) * | 1998-01-13 | 1999-09-14 | Synchroneuron | Methods of treating tardive dyskinesia and other movement disorders |
| JP4562911B2 (en) * | 1998-01-13 | 2010-10-13 | シンクロニュ−ロン，エルエルシ− | Method for treating tardive dyskinesia and other movement disorders |
| ES2209110T3 (en) * | 1998-01-27 | 2004-06-16 | Merck Sante | NEW DERIVATIVES OF SULFONIC, PHOSPHONIC AND PHOSPHINIC ANINOALCAN ACIDS, THEIR PREPARATION AND THEIR USE AS MEDICATIONS. |
| US20020022657A1 (en) * | 1998-02-11 | 2002-02-21 | Francine Gervais | Methods for modulating neuronal cell death |
| FR2775188B1 (en) * | 1998-02-23 | 2001-03-09 | Lipha | IMMEDIATE RELEASE ORAL EXTENDED RELEASE GALENIC FORM COMPRISING AN ABSORPTION PROMOTING AGENT AND USE OF THE ABSORPTION PROMOTING AGENT |
| EP1276483B1 (en) * | 1999-04-28 | 2009-09-02 | BELLUS Health (International) Limited | Compositions and methods for treating amyloidosis using sulphonate derivatives |
| US6562836B1 (en) * | 1999-05-24 | 2003-05-13 | Queen's University Of Kingston | Methods and compounds for inhibiting amyloid deposits |
| US20070010573A1 (en) * | 2003-06-23 | 2007-01-11 | Xianqi Kong | Methods and compositions for treating amyloid-related diseases |
| US7414076B2 (en) * | 2003-06-23 | 2008-08-19 | Neurochem (International) Limited | Methods and compositions for treating amyloid-related diseases |
| US7244764B2 (en) * | 2003-06-23 | 2007-07-17 | Neurochem (International) Limited | Methods and compositions for treating amyloid-related diseases |
| AU2005310986A1 (en) * | 2004-11-12 | 2006-06-08 | Bellus Health (International) Limited | Methods and fluorinated compositions for treating amyloid-related diseases |
| EP1817305A2 (en) * | 2004-11-16 | 2007-08-15 | Neurochem (International) Limited | Compounds for the treatment of cns and amyloid associated diseases |
| BRPI0519243A2 (en) * | 2004-12-22 | 2009-01-06 | Neurochem Int Ltd | Methods and compositions for treating amyloid-related diseases |
| TW200716088A (en) * | 2005-04-15 | 2007-05-01 | Neurochem Int Ltd | Formulations and methods for treating amyloidosis |
| MX2008008213A (en) * | 2005-12-22 | 2008-09-03 | Neurochem Int Ltd | Treatment of renal disorders, diabetic nephopathy and dyslipidemias. |
| FI3851447T3 (en) | 2006-10-12 | 2023-11-15 | Bellus Health Inc | Methods, compounds, compositions and vehicles for delivering 3-amino-1-propanesulfonic acid |
| EP2120905A1 (en) * | 2006-12-22 | 2009-11-25 | BELLUS Health (International) Limited | Methods, compounds, and compositions for treating metabolic disorders and diabetes |
| KR100877134B1 (en) * | 2007-05-03 | 2009-01-09 | 주식회사 엔지켐 | Process for preparation of Acamprosate Calcium |
| TW200924748A (en) * | 2007-09-07 | 2009-06-16 | Xenoport Inc | Masked carboxylate neopentyl sulfonyl ester cyclization release prodrugs of acamprosate, compositions thereof, and methods of use |
| US20090082464A1 (en) * | 2007-09-07 | 2009-03-26 | Bernd Jandeleit | Externally masked neopentyl sulfonyl ester cyclization release prodrugs of acamprosate, compositions thereof, and methods of use |
| WO2009052191A1 (en) * | 2007-10-15 | 2009-04-23 | Xenoport, Inc. | Internally masked neopentyl sulfonyl ester cyclization release prodrugs of acamprosate, compositions thereof, and methods of use |
| CN101492400B (en) * | 2008-01-22 | 2014-03-12 | 北京华禧联合科技发展有限公司 | Method for preparing high-purity acamprosate calcium |
| DE102008048791A1 (en) | 2008-09-24 | 2010-03-25 | Merck Patent Gmbh | New crystal form of calcium 3-acetylaminopropane-1-sulfonate |
| IT1392327B1 (en) * | 2008-09-26 | 2012-02-28 | Laboratorio Chimico Int Spa | NEW POLIMORPHIC SHAPE OF CALCIUM ACAMPROSEE |
| CN104478766A (en) * | 2014-12-25 | 2015-04-01 | 北京华禧联合科技发展有限公司 | Method for preparing high-purity acetyl homotaurine |
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| US3039916A (en) * | 1961-03-27 | 1962-06-19 | West Laboratories Inc | Anionic iodine complexes |
| US3544597A (en) * | 1969-06-12 | 1970-12-01 | Rohm & Haas | Process for manufacturing sulfonated amides |
| JPS5418714B2 (en) * | 1974-10-08 | 1979-07-10 | ||
| FR2321285A1 (en) * | 1975-08-18 | 1977-03-18 | Stanley Drug Products Inc | Fibrinolytic aminoalkane sulphonic acids - prepd. e.g. from dibromoalkane and sodium sulphite and ammonia |
| FR2384751A1 (en) * | 1977-03-23 | 1978-10-20 | Francaise Coop Pharma | NEW DERIVATIVES OF TAURINE WITH ENHANCED NEUROMUSCULAR ACTIVITY |
| US4233229A (en) * | 1978-01-03 | 1980-11-11 | Gaf Corporation | Preparation of salt-free N-acyl taurines |
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1979
- 1979-05-23 FR FR7913207A patent/FR2457281A1/en active Granted
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1980
- 1980-05-19 US US06/150,946 patent/US4355043A/en not_active Expired - Lifetime
- 1980-05-20 GR GR62000A patent/GR68547B/el unknown
- 1980-05-21 DE DE19803019350 patent/DE3019350A1/en active Granted
- 1980-05-21 DE DE1996175017 patent/DE19675017I2/en active Active
- 1980-05-22 MA MA19051A patent/MA18855A1/en unknown
- 1980-05-22 ZA ZA00803051A patent/ZA803051B/en unknown
- 1980-05-22 IT IT67807/80A patent/IT1130455B/en active
- 1980-05-22 AT AT0274580A patent/AT372371B/en not_active IP Right Cessation
- 1980-05-22 GB GB8016956A patent/GB2051789B/en not_active Expired
- 1980-05-22 CH CH3998/80A patent/CH647757A5/en not_active IP Right Cessation
- 1980-05-23 ES ES491787A patent/ES491787A0/en active Granted
- 1980-05-23 NL NL8002997A patent/NL191789C/en not_active IP Right Cessation
- 1980-05-23 JP JP6796380A patent/JPS5625146A/en active Granted
- 1980-05-23 BE BE0/200755A patent/BE883468A/en not_active IP Right Cessation
- 1980-05-23 AU AU58697/80A patent/AU535785B2/en not_active Expired
- 1980-05-23 OA OA57119A patent/OA06606A/en unknown
- 1980-05-23 CA CA000352613A patent/CA1152100A/en not_active Expired
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1990
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1992
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Also Published As
| Publication number | Publication date |
|---|---|
| DE3019350C2 (en) | 1989-11-30 |
| JPH0317825B2 (en) | 1991-03-11 |
| AT372371B (en) | 1983-09-26 |
| MX9203363A (en) | 1992-07-01 |
| AU5869780A (en) | 1980-11-27 |
| JPH03148219A (en) | 1991-06-25 |
| NL970003I2 (en) | 1997-08-01 |
| FR2457281A1 (en) | 1980-12-19 |
| ATA274580A (en) | 1983-02-15 |
| ZA803051B (en) | 1981-06-24 |
| AU535785B2 (en) | 1984-04-05 |
| IT1130455B (en) | 1986-06-11 |
| GR68547B (en) | 1982-01-18 |
| BE883468A (en) | 1980-11-24 |
| ES8101042A1 (en) | 1980-12-16 |
| FR2457281B1 (en) | 1983-10-07 |
| US4355043A (en) | 1982-10-19 |
| DE19675017I2 (en) | 2001-04-26 |
| DE3019350A1 (en) | 1980-12-04 |
| NL970003I1 (en) | 1997-04-01 |
| NL191789B (en) | 1996-04-01 |
| GB2051789B (en) | 1983-04-27 |
| NL8002997A (en) | 1980-11-25 |
| MA18855A1 (en) | 1980-12-31 |
| NL191789C (en) | 1996-08-02 |
| ES491787A0 (en) | 1980-12-16 |
| OA06606A (en) | 1981-08-31 |
| IT8067807A0 (en) | 1980-05-22 |
| GB2051789A (en) | 1981-01-21 |
| CH647757A5 (en) | 1985-02-15 |
| JPH0524135B2 (en) | 1993-04-06 |
| JPS5625146A (en) | 1981-03-10 |
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