CA1204448A - Secretin preparations with intensified and protracted action, process for their manufacture, their use as well as dihydroxy-benzoyl-l-tyrosine - Google Patents
Secretin preparations with intensified and protracted action, process for their manufacture, their use as well as dihydroxy-benzoyl-l-tyrosineInfo
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- CA1204448A CA1204448A CA000416529A CA416529A CA1204448A CA 1204448 A CA1204448 A CA 1204448A CA 000416529 A CA000416529 A CA 000416529A CA 416529 A CA416529 A CA 416529A CA 1204448 A CA1204448 A CA 1204448A
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- tyrosine
- secretion
- dihydroxybenzoyl
- depot
- acid
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Abstract
Abstract of the Disclosure This application is directed to dihydroxybenzoyl-L-tyrosines and to a process for their preparation by the reaction of a dihydroxybenzoic acid with an acid addition salt of L-tyrosine-alkylester in the presence of an amine and the hydrolysis of the resultant dihydroxybenzoyl-L-tyrsine-alkylester. The compounds are useful in the preparation of secretin preparations having an intensified and protracted action.
Description
~4448
- 2 HOE 79/F 144 K
_ _ The invention relates to secretion preparations with an intensified and protracted action, especially secretion preparations which may be administered subcutaneously and rectally.
Attempts have been made again and again to protract the short action of the hormone secretion by suitable injection compositions. So far, only one preparation showing this quality has been described, namely a combo-session of secreting polyphloretin phosphate (PUP) and gelatin derivatives (German Patent No. 2,104,344).
The effect of PUP is attributed to its hyaluronidase-inhibiting action and to its capability of binding the basic secreting The effect of the gelatin derivative is seen in an additional delay of the secretion absorption, with adduce formation also being observed. With these preparations there is the risk of undesirable reactions due to a deposit of PUP in the tissue.
Many medicaments may be incorporated in suppositories and administered rectally. They are sufficiently well absorbed in this form. For peptizes, suppositories or rectal capsules do not represent a suitable form of application, since in this case the rate of absorption is too low for normal practice. For example, if secretion is administered by this route, the biological effect which is measured via the pancreatic juice secretion is only about 1 % of the effect obtained with subcutaneous injection.
Surprisingly, it has now been found that phenol bodies which do not show any hyaluronidase inhibition and are of low molecular weight (when compared with PUP) intent sift and prolong the secretion action of secretion injection preparations in viva.
It has also been found that the available amount O r secretion may be considerably increased in the case of rectal application in suppositories, if certain finlike compounds are added to the suppository mass. At the same time said compounds prolong the action of the secreting as this has been observed also for secretion injection .
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_ _ The invention relates to secretion preparations with an intensified and protracted action, especially secretion preparations which may be administered subcutaneously and rectally.
Attempts have been made again and again to protract the short action of the hormone secretion by suitable injection compositions. So far, only one preparation showing this quality has been described, namely a combo-session of secreting polyphloretin phosphate (PUP) and gelatin derivatives (German Patent No. 2,104,344).
The effect of PUP is attributed to its hyaluronidase-inhibiting action and to its capability of binding the basic secreting The effect of the gelatin derivative is seen in an additional delay of the secretion absorption, with adduce formation also being observed. With these preparations there is the risk of undesirable reactions due to a deposit of PUP in the tissue.
Many medicaments may be incorporated in suppositories and administered rectally. They are sufficiently well absorbed in this form. For peptizes, suppositories or rectal capsules do not represent a suitable form of application, since in this case the rate of absorption is too low for normal practice. For example, if secretion is administered by this route, the biological effect which is measured via the pancreatic juice secretion is only about 1 % of the effect obtained with subcutaneous injection.
Surprisingly, it has now been found that phenol bodies which do not show any hyaluronidase inhibition and are of low molecular weight (when compared with PUP) intent sift and prolong the secretion action of secretion injection preparations in viva.
It has also been found that the available amount O r secretion may be considerably increased in the case of rectal application in suppositories, if certain finlike compounds are added to the suppository mass. At the same time said compounds prolong the action of the secreting as this has been observed also for secretion injection .
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- 3 - HOE 79/F 144 K
- preparations.
Thus, the present invention provides a secretion preparation with an intensified and protracted action, which contains a finlike depot body showing a molecular weight of up to about 2,000 and having one or several Bunsen nuclei with at least one finlike OH group, wherein the nucleus carrying the finlike group may also be condensed to a hydroxynaphthyl, a hydroxyindole or a hydroxyquinoline radical.
In the above and the following passages the term of secretion includes natural and synthetic secreting en-specially in the form of physiologically acceptable salts, for example hydrochloride, acetate or citrate. Besides, by finlike depot bodies there are to be understood in the above and the following passages the finlike come pounds to be used in accordance with the invention. The invention relates especially to secretion injection pro-portions and rectally administrable secretion prepare-lions.
By applying the finlike depot bodies as defined above the risk of a deposit of higher molecular compounds in the tissue is avoided which might lead to undesirable reactions. The protracted and intensified action of secretion becomes already clearly evident with phenol itself. Yet compounds with several finlike groups and Bunsen nuclei show a stronger effect. By varied sub-stitution the degree of efficacy is modified without a recognizable pattern. A marked prolongation of efficacy is always bound to the presence of at least one free finlike group in the molecule. The effects in sub-cutaneous and rectal application are not always parallel.
Thus, for example, a typical compound, namely Dow-hydroxy-benzoyl-L-tyrosine, leads to a higher increase in efficacy when applied rectally than with subcutaneous application.
The depot bodies used according to the invention contain preferably from 1 to 12 Bunsen nuclei, with one or several of these nuclei containing up to 3 finlike I
- preparations.
Thus, the present invention provides a secretion preparation with an intensified and protracted action, which contains a finlike depot body showing a molecular weight of up to about 2,000 and having one or several Bunsen nuclei with at least one finlike OH group, wherein the nucleus carrying the finlike group may also be condensed to a hydroxynaphthyl, a hydroxyindole or a hydroxyquinoline radical.
In the above and the following passages the term of secretion includes natural and synthetic secreting en-specially in the form of physiologically acceptable salts, for example hydrochloride, acetate or citrate. Besides, by finlike depot bodies there are to be understood in the above and the following passages the finlike come pounds to be used in accordance with the invention. The invention relates especially to secretion injection pro-portions and rectally administrable secretion prepare-lions.
By applying the finlike depot bodies as defined above the risk of a deposit of higher molecular compounds in the tissue is avoided which might lead to undesirable reactions. The protracted and intensified action of secretion becomes already clearly evident with phenol itself. Yet compounds with several finlike groups and Bunsen nuclei show a stronger effect. By varied sub-stitution the degree of efficacy is modified without a recognizable pattern. A marked prolongation of efficacy is always bound to the presence of at least one free finlike group in the molecule. The effects in sub-cutaneous and rectal application are not always parallel.
Thus, for example, a typical compound, namely Dow-hydroxy-benzoyl-L-tyrosine, leads to a higher increase in efficacy when applied rectally than with subcutaneous application.
The depot bodies used according to the invention contain preferably from 1 to 12 Bunsen nuclei, with one or several of these nuclei containing up to 3 finlike I
- 4 - HOE 79/F 144 K
_ hydroxy groups. It is not required that all phenol radix eels of a molecule carry finlike groups. The phenol radicals may be condensed to hydroxynaphthyl, hydroxy-insole or hydroxyquinoline radicals.
Besides, the phenol radicals present in the molecule may be condensed and/or bound to one another directly and/or via bridge members. Bridge members of this kind are for example alkyd, ether, thither, carbonamides, sulfoxides, cellophane, urethane, disulfide, sulfonamide, acetone, phosphoric acid ester and alkylphosphine oxide.
The bridge members show 8 atoms at a maximum in linear order, or in the case of alkyd the alkyd radicals have up to 8 carbon atoms. The phenol radicals - including those which carry OH groups - and the bridge members may be further substituted be alkyd, cycloalkyl, hydroxyalky', halogen, vitro, car boxy, carbonamido, sulfonic acid, sulfonamide, alkyd sulfoxide, alkyd cellophane, phosphoric acid ester, phosphoric acid, dialkylphosphine oxide Andre alkylphosphonic acid. If these substituents include alkyd groups, said alkyd groups have up to 8 carbon atoms.
If phenylcarboxylic acid radicals are present in the depot body, they may be bound to polyamides like acid asides.
A decisive factor for the efficacy of the depot bodies employed is not to be seen in the substituents optionally present, but in the presence of one or several finlike OH groups.
An additional prolongation of the secretion effect in the preparations that may be administered subcutane-ouzel is ensured by the fact that the preparation contains, besides a finlike physiologically acceptable depot body, a gelatin derivative which is prepared either 1. by a reaction of collagen degradation products of a molecular weight of from 2000 to 20,000 with an amount of diisocyanate smaller than that correspond ding to the number of the amino and guanidino groups present in the degraded collagen, at O to 100C in the neutral or slightly alkaline range and subsequent 1;Z~4~4~
....
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adjustment of the cross-linked product to a pi value of 7 and to isotonicity by way of sodium chloride, or 2. by a further degradation of the cross-linked pro-duct obtained according to step 1) in aqueous solution at 60 to 150C up to a molecular weight of from 10,000 to 100,00p and subsequent adjust-mint to pi 7 and isotonicity according to I above.
Secretion preparations for subcutaneous application which contained the depot bodies specified in the folio-wing Tale were tested in animal experiments. In the experimental procedure chosen, 5 to 8 male rats weighing 300 to 500 g each are administered subcutaneously 5 CU/kg of secretion tCU means clinical unit) and 10 my of the depot body to be tested each in aqueous solution or suspension. As solubilizers there are used Methyl pyrrolidone, dim ethyl sulfoxide, dim ethyl formamide, tetrahydrofur~uryl alcohol-polyethylene glycol ether, polyethylene glycol, 1,3-butylene-glycol or 1,2-propylene glycol, which by themselves do not involve any intense-ligation of the secretion effect.
The animals remain without food for 18 hours prior to the test, but they are given water ad lobotomy. Under urethane anesthesia (5 ml/kg I'm. of 25 urethane) the abdomen is opened by median section after tracheotomy, and the pullers is ligated. The ducts choledochus is tied off in its proximal part near the port hepatis, and the bile is led into the duodenum via a polyethylene tube of a diameter of 0.05 mm. A Connally or catheter is inserted into the distal part of the bile duct, into which the numerous pancreatic ducts open, immediately before it opens into the duodenum, and the volume of the secretion running off is measured in 60 minute intervals.
Following a preliminary run of 60 minutes the prepare-us lions are administered.
In the following Table, column 1 shows the depot body, column 2 the method of preparation. L means the compound known from literature and characterized by the ~2~44~
- 6 - JOE 79~F 144 K
-melting point, optionally US, IT or NOR. A to C relate to the preparation according to Example 1, process A to CO These compounds were characterized by ultimate analysis. The third column indicates the percentage by which the pancreatic secretion is above the basal secretion after 5 hours (calculated on the control =
100 %). This value is a measure for the depot effect of the depot body tested. Column 4 indicates the intensify-cation of the secretion effect, with the total pancreatic juice secretion having been given over 5 hours as compared with the control (0.9 % of Maul) = 1.
TABLE
Pancreatic 'vice secretion of the rat after subcutan.
administration of 5 CU/kg of secretion with different depot bodies (10 mg/animal~
Of Depot body Prepare- % vs. ~el.Intensity lion control of effect over S hours Phenol L 51 8 ResorcLnol L 55 6.1 Pyrogallol L 41 5.1 Phloroglucine L 15 6.6 2-Hydroxyacetophenone L 38 OWE
3-Hydroxy-acetophene L 54 9.0 4-Hyd~oxyacetophenone L 43 8.1 2,4-Dihydroxy-acetophenone L 70 6.1 2-Hydroxy-benzophenone L 74 7.2 3-Hydroxy-benzophenone L 79 8.0 4-Hydroxybenzophenone L 70 6.7 2,4-Dihydroxy-benzophenone L 163 9.1 2,2'-4,4'-Tetrahydroxybenzophenone L 58 4.8 2,3,4-Trihydroxy-benzophenone L 109 9.1 Phloretin L 180 8.2 4,4'-Dihydroxy-diphenyl cellophane L 74 6.2 4-Hydroxyphenylmethyl sulfoxide L 96 12.3 4-Hydroxyphenylmethyl cellophane L 8 6.0 4-Hydroxybenzene-sulfonic acid-Na L 18 2.7 Phloretin monophosphate L 65 7.7 Bis-phloretin phosphate L 56 2.5 Phloretin-3,5-dinethylphenyl L 68 3.7 phosphate 3,5-Dihydroxyphenylcarbonyl- L 62 3.4 ethylphenyl-3,5-dimethyl phosphate 2-Hydroxy-quinolir.~-4-carboxylic L 5 5.0 acid 8-Hydroxyquinoline L 37 4.7 2-Hydroxy-benzoic acid L 6 4.5 2-Hydroxy-benzoic acid amid L 51 8.0 3-Hydroxy~enzoic acid L 47 4.0 4-Hydroxybenzoic acid L 38 3.8 ~2~4~
-Depot body Proper- I% vs. Rel.Intensity lion control of effect aver
_ hydroxy groups. It is not required that all phenol radix eels of a molecule carry finlike groups. The phenol radicals may be condensed to hydroxynaphthyl, hydroxy-insole or hydroxyquinoline radicals.
Besides, the phenol radicals present in the molecule may be condensed and/or bound to one another directly and/or via bridge members. Bridge members of this kind are for example alkyd, ether, thither, carbonamides, sulfoxides, cellophane, urethane, disulfide, sulfonamide, acetone, phosphoric acid ester and alkylphosphine oxide.
The bridge members show 8 atoms at a maximum in linear order, or in the case of alkyd the alkyd radicals have up to 8 carbon atoms. The phenol radicals - including those which carry OH groups - and the bridge members may be further substituted be alkyd, cycloalkyl, hydroxyalky', halogen, vitro, car boxy, carbonamido, sulfonic acid, sulfonamide, alkyd sulfoxide, alkyd cellophane, phosphoric acid ester, phosphoric acid, dialkylphosphine oxide Andre alkylphosphonic acid. If these substituents include alkyd groups, said alkyd groups have up to 8 carbon atoms.
If phenylcarboxylic acid radicals are present in the depot body, they may be bound to polyamides like acid asides.
A decisive factor for the efficacy of the depot bodies employed is not to be seen in the substituents optionally present, but in the presence of one or several finlike OH groups.
An additional prolongation of the secretion effect in the preparations that may be administered subcutane-ouzel is ensured by the fact that the preparation contains, besides a finlike physiologically acceptable depot body, a gelatin derivative which is prepared either 1. by a reaction of collagen degradation products of a molecular weight of from 2000 to 20,000 with an amount of diisocyanate smaller than that correspond ding to the number of the amino and guanidino groups present in the degraded collagen, at O to 100C in the neutral or slightly alkaline range and subsequent 1;Z~4~4~
....
'; - 5 - HOE 79/F 144 X
adjustment of the cross-linked product to a pi value of 7 and to isotonicity by way of sodium chloride, or 2. by a further degradation of the cross-linked pro-duct obtained according to step 1) in aqueous solution at 60 to 150C up to a molecular weight of from 10,000 to 100,00p and subsequent adjust-mint to pi 7 and isotonicity according to I above.
Secretion preparations for subcutaneous application which contained the depot bodies specified in the folio-wing Tale were tested in animal experiments. In the experimental procedure chosen, 5 to 8 male rats weighing 300 to 500 g each are administered subcutaneously 5 CU/kg of secretion tCU means clinical unit) and 10 my of the depot body to be tested each in aqueous solution or suspension. As solubilizers there are used Methyl pyrrolidone, dim ethyl sulfoxide, dim ethyl formamide, tetrahydrofur~uryl alcohol-polyethylene glycol ether, polyethylene glycol, 1,3-butylene-glycol or 1,2-propylene glycol, which by themselves do not involve any intense-ligation of the secretion effect.
The animals remain without food for 18 hours prior to the test, but they are given water ad lobotomy. Under urethane anesthesia (5 ml/kg I'm. of 25 urethane) the abdomen is opened by median section after tracheotomy, and the pullers is ligated. The ducts choledochus is tied off in its proximal part near the port hepatis, and the bile is led into the duodenum via a polyethylene tube of a diameter of 0.05 mm. A Connally or catheter is inserted into the distal part of the bile duct, into which the numerous pancreatic ducts open, immediately before it opens into the duodenum, and the volume of the secretion running off is measured in 60 minute intervals.
Following a preliminary run of 60 minutes the prepare-us lions are administered.
In the following Table, column 1 shows the depot body, column 2 the method of preparation. L means the compound known from literature and characterized by the ~2~44~
- 6 - JOE 79~F 144 K
-melting point, optionally US, IT or NOR. A to C relate to the preparation according to Example 1, process A to CO These compounds were characterized by ultimate analysis. The third column indicates the percentage by which the pancreatic secretion is above the basal secretion after 5 hours (calculated on the control =
100 %). This value is a measure for the depot effect of the depot body tested. Column 4 indicates the intensify-cation of the secretion effect, with the total pancreatic juice secretion having been given over 5 hours as compared with the control (0.9 % of Maul) = 1.
TABLE
Pancreatic 'vice secretion of the rat after subcutan.
administration of 5 CU/kg of secretion with different depot bodies (10 mg/animal~
Of Depot body Prepare- % vs. ~el.Intensity lion control of effect over S hours Phenol L 51 8 ResorcLnol L 55 6.1 Pyrogallol L 41 5.1 Phloroglucine L 15 6.6 2-Hydroxyacetophenone L 38 OWE
3-Hydroxy-acetophene L 54 9.0 4-Hyd~oxyacetophenone L 43 8.1 2,4-Dihydroxy-acetophenone L 70 6.1 2-Hydroxy-benzophenone L 74 7.2 3-Hydroxy-benzophenone L 79 8.0 4-Hydroxybenzophenone L 70 6.7 2,4-Dihydroxy-benzophenone L 163 9.1 2,2'-4,4'-Tetrahydroxybenzophenone L 58 4.8 2,3,4-Trihydroxy-benzophenone L 109 9.1 Phloretin L 180 8.2 4,4'-Dihydroxy-diphenyl cellophane L 74 6.2 4-Hydroxyphenylmethyl sulfoxide L 96 12.3 4-Hydroxyphenylmethyl cellophane L 8 6.0 4-Hydroxybenzene-sulfonic acid-Na L 18 2.7 Phloretin monophosphate L 65 7.7 Bis-phloretin phosphate L 56 2.5 Phloretin-3,5-dinethylphenyl L 68 3.7 phosphate 3,5-Dihydroxyphenylcarbonyl- L 62 3.4 ethylphenyl-3,5-dimethyl phosphate 2-Hydroxy-quinolir.~-4-carboxylic L 5 5.0 acid 8-Hydroxyquinoline L 37 4.7 2-Hydroxy-benzoic acid L 6 4.5 2-Hydroxy-benzoic acid amid L 51 8.0 3-Hydroxy~enzoic acid L 47 4.0 4-Hydroxybenzoic acid L 38 3.8 ~2~4~
-Depot body Proper- I% vs. Rel.Intensity lion control of effect aver
5 hours 4-Hydroxy-benzoic acid-methyl-ester L 15 5.3 4-Hydroxy-benzyl alcohol L 12 1~3 3,5-Dihydroxybenzoic acid-3-hydroxy- B 49 6.2 aniline 2,4-Dihydroxybenzoic acid L 28 7.1 3,4,5JTrihydroxybenzoic acid L 28 5.
3,5-Dihydroxybenzoic acid L 25 6.6 3,5-Dihydro~ybenzoic acid aside L 34 6.2 2,4-Dihydroxybenzoic acid-benzylamide L 64 6.8 Bis-(2,4-dihydroxybenzoyl-)-diamuno- B 69 6.5 ethanes Bis-(3,5-dihydroxybenzoyl)-diamino- A 79 6.1 ethanes Bis-(2-hydroxybenzoyl)-diaminoethane A 72 5.9 Bis-(2,4-dihydroxybenzoyl)-1,4-di- B 83 6.7 amino butane Bis-(3,5-dihydroxybenzoyl)-1,4- AHAB 85 7.4 diaminobutane Tris-(2-hydroxybenzoyl)-diethylene- B 62 8.1 . thiamine Tris-(3-hydroxybenzoyl)-diethylene- A 71 8.0 thiamine Tris-(4-hydroxybenzoyl)-diethylene- B 68 7.8 trim me Tris-(3,5-dihydroxybenzoyl-diethylene- A 79 8.6 Truman Tetra-(2-hydroxybenzoyl)-triethylene- A 91 OWE
tetramine Tetra-(3-hydroxybenzoyl-)triethylene- A 95 9.1 tetramine Tetra-`13,5-dih~drox~enzoyl)-tri- A 101 9.7 ethylene-tetr~nine Tetra-(2,6-dihydroxybenzoyl)-tri- B 78 8.1 ethylene-tetramine ~,6~4~
- g -- HOE 79/F 144 K
Depot body Prepare- % vs. Rot. Intensity lion control ox effect over 5 hours .. . _ . ...
2,8-Dihydroxy-3-naphthoyl-di- B 77 9.1 ethanol amine Tris-(2,8-dihydroxy-3-naphthoyl)- B 94 9.4 diethylene-triamine 1-Hydroxy-2-naphthoic acid-diethanol- AHAB 79 8.1 aside 1-Hydroxy-2-naphthoic acid-ethanol- AHAB 74 8.0 aside 2-Hydroxy-5-chloro-benzoic acid- A 77 7.3 diethanolamide Bis-(3,5-dihydroxyben2oyl)-cys~amine AHAB 79 By 3-~2-Hydroxybenzoylamino)-benzene- A 81 8.1 sulfonamide Tetra-(3,5-dihydroxybenzoyl-L- A 98 OWE
tyrosyl)-triethylene-tetramine 3,5-Dihydroxybenzoyl-aminomethyl- A 75 8.9 phosphoric acid 2,4-Dihydroxyb~nzoyl-aminomethvl~ B 79 8.6 dimethylphosph me oxide 2,4-Dihydroxybenzoyl-L-tyrosine- B 70 7 . 8 ethyl ester N No ~-Bis(3,5-dihydroxybenzoyl-L- C 86 8.8 tyrosyl)-L-lysine-diethanol-amide Ben~-loxycarbonyl-L-tyrosine L 7 5.9 3,5-Dihydroxybenzoyl-L-tyrosine B 76 9.2 2,4-Dihydroxybenzoyl-L-tyrosine B 84 10.5 2,4-Dihydrox~-benzoyl-L-tyrosine-n- C 87 8.7 butylamide 3,5-Dihydroxybenzoyl-L-tyrosine-di- C 76 7.6 ethanolamide 2,4-Dihydroxykenzoyl-L,tyrosine-di- C 47 8.7 ethanolamide Bis-(benzylo~carbonyl-L-~y.rosine)- C 44 SO
diaminoethane 12~4~4~
Depot body Prepare- I% vs. Rel.Int~sity lion control of effect o'er S his . _ . . . .
Bis-(3,5-dihydroxy~enzoyl-L-tyrosine)- C 58 7.0 diaminoethane Bis-(2~bcxybenzoyl-L-tyrosine)- C - 48 6.3 diaminoethane Bis-(2,4~hydroxybenzoyl-L,tyrosine)- C 82 6.0 diaminoethane Bis-~3-benzoylpropionyl-L-tyrosine)- C 60 3.7 diaminoethane Eenzyloxycarbonyl-L-tyrosyl-L-ty~o- L 62 7.5 sine No -Bis-(benzyloxycar~onyl-Lr C 48 7.0 tyrosyl)-L-lysine N No -Bis-(benzyloxycarbonyl-L- C 13 1.5 tyrosyl)-D-lysine N No -Bis-(benzyloxycarbonyl-L- C 93 8.2 tyrosyl)-L-lysine-methyl ester NUN -Bis-(benzyloxycarbonyl-L- C 90 8.4 tyrosyl)-L-lysine-amide As may be seen from the Tables, all finlike depot bodies tested have a protracting and intensifying in-fluency on the secreting The depot bodies which may be employed according to the invention are either compounds known from literature or those wish are prepared for example in accordance with the methods described in the experimental part. It is a great advantage that even low-molecular compounds of simple structure which may easily be obtained are suitable depot bodies.
The fact that these finlike depot bodies are not only present in admixture with secreting but also form addition products with the latter, may easily be seen from the drastic reduction of the molecular extinction of the phenols in the proximity of 280 no by up to 50 %, 1~44~
while adding increasing amounts of secreting however, since the said adduce formation is fever-sidle and subject to the law of mass action, it is ad-vintages to use a large molar excess of depot bodies.
For the subcutaneous administration in humans, from 10 to 100 my of a depot body in 1 to 2 ml of solution or suspension are used per 80 to 1000 clinical units (CUT; 1 my of secretion = 4000 CUT according to Gut 19 (1978, page 355~, 1 my of secretion is reported to have a biological effect corresponding to 5000 CUT). If a gelatin derivative is added to improve the effect, its concentration is from 30 to 100 mg/ml. Also the gelatin derivatives optionally present in the secretion reduce the US extinction of the phenols and are thus present in a complex bond. For preparing the adduces and mix-uses it is sufficient to bring the components into contact with one another for a short time in a solution. The adduce formation takes place rapidly.
As finlike depot bodies for the rectally ad mini-storable secretion preparations there may also be used those specified in the Table.
It is a great advantage also for this type of pro-parathion that already low-molecular compounds of simple structure which are easily accessible are suitable to increase the available amount of secretion from suppose-tories or rectal capsules in a way that a rectal apply-cation of secretion becomes possible or useful for the first time. The reversible adduce formation mentioned before also takes place, and it is equally advantageous to use a large molar excess of depot bodies.
The intensified effect of secretion in the form of rectally administrable preparations due to the depot bodies used according to the invention becomes evident from the drawing. In a test carried out on 8 rats each weighing 0.5 kg, 100 go of secretion in a suppository of a weight of 73 my cause the production of 92 Al of pancreatic juice (curve 1). With the addition of 25 my of 3,5-dihydroxybenzoyl-L-tyrosine the volume of pane-retook juice rose to 1778 Al (curve 2). This corresponds 4~48 to an increase of the effect to about 20 times its original value. Besides, a protracted action can also be observed. In the present case the secretion dose has been chosen very high, in order to obtain a measurable Sol-use also without additive.
With a non-maximum stimulation in the normal dose range (about half the dose), the increase of the effect is about 50-fold.
For the treatment of humans, from about 0.1 to 2 my of secretion are required per suppository (= 400 to 8000 clinical units CUT 1 my of secretion = 4000 CUT according to Gut 19 (1978), page 355, 1 my of secretion is stated to have a biological effect corresponding to 5000 CUT).
The minimum amount of depot bodies is about 50 my. The maximum amount is determined by the processibility. For a suppository of a weight of about 2 g it is up to 1 to 1.5 g, Another subject of the invention is a process for the manufacture of a secretion preparation having a pro-treated and intensified action.
A subcutaneously administrable preparation of the invention is preferably obtained by dissolving secretion hydrochloride prepared according to US Patent No.
4,098,779 (corresponding to German Offenlegungsschrift No. 2,615,229) in water or in the aqueous solution of one of the above-specified gelatin derivatives and come brining the resulting solution with the solution of the depot body in water. In this process the pi value is in the range of from 7 to 8.5. It is adjusted to 7.0 to 7.8 with a physiologically acceptable acid, whereupon the solution is lyophilized.
Some depot bodies are sparingly soluble and are - present under the above conditions in a suspension. In this case an amorphous or crystalline suspension is pro-us pared by precipitation of the phenols dissolved at pi 10 and adjustment of the pi to the range between 7.0 and 7.4, which suspension may be stabilized by the presence of a gelatin derivative as defined above. This suspension is combined with the aqueous solution of secreting or I
- 13 - HOE 79/F 1~4 X
lyophilized secretion is dissolved in this aqueous suspension. Already after a short time the secretion has been fully adsorbed to the depot body. This secreting containing suspension should be injected within one week.
Furthermore, it is also possible to dissolve the finlike depot bodies in water containing up to 30 % of a solubilizer. Suitable solubilizers are 1,2-propylene glycol, battalion glyc~l, polyethylene glycol, twitter-hydrofurfuryl alcohol-polyethylene glycol ether, dim ethyl sulfoxide, N-methyl pyrrolidone or dim ethyl formamide.
In this case the solution of the depot carrier is prefer-ably prepared without secreting and said solution which is not lyophilized is filled into ampules of preferably 1 to 2 ml. In a second ampule the secretion is present in a lyophilized state. Immediately prior to application the secretion is dissolved in the solution of the depot carrier, whereupon the adduce is formed. A gelatin don-votive may optionally be added to the secretion or the depot body or both.
The process for the manufacture of rectally ad mini-storable secretion preparations with protracted and intent silted action comprises preparing suppositories or rectal capsules from a mixture of a generally common carrier, secretion and a phènolic depot body as kirk-terraced above.
As suppository mass there are used known compounds, for example partial glycerides, i.e. mixtures of moo-and divesters of glycerol with higher fatty acids, further-more fatty acid-1,2-propylene-glycol esters, and more-over polyethylene glycols with a solidification range of from about 30 to 50C. The secretion suspension in-corporate into masses of this kind or into oil, to-getter with the phenols to be used according to the invention, may also be filled off into commercial rectal capsules.
The suppositories are manufactured by homogenizing the mixture of carrier, secretion and a phenol to be used according to the invention in the melt and subset 41~3 quaintly filling it into suppository molds, while being still in the liquid state, in which molds said mixture is allowed to solidify. Semisolid or oily suspensions are filled into rectal capsules. The weight of a suppository is from about 1 to 3 g.
In a similar manner it is also possible to menu-lecture suppositories on the basis of glycerol and gelatin.
Suppository masses such as fatty acid-1,2-propylene glycol ester are mixed together with secretion and a depot body to be used according to the invention and molded into granules without melting. The suppositories or rectal capsules of the invention are used for treating and preventing hemorrhages of the intestinal tract and for the treatment of ulcer. They represent the first secretion preparation not to be administered any longer by injection The invention relates further to the finlike compounds specified in the Table which have not yet been described in literature, which may be prepared according to the processes indicated above and are used as depot bodies for the secretion preparations of the invention. A special subject of this invention is 3,5-dihydroxybenzoyl-L-tyrosine.
Finlike depot bodies with carbonamide groups are synthesized according to common methods for the prepare-lion of carbonamide compounds, if they have not been known from literature.
Particularly suitable and easily accessible depot bodies, as they are specified in the Table, may by pro-pared for example from hydroxyl group-~arrying car boxy-fig acids and amine. Amine components may also be amine optionally carrying hydroxyl groups, amino acid esters, peptize esters or amino acid- or peptize asides.
If the amine components contain carboxylic acid groups, the latter are advantageously prepared from the corresponding esters, in most cases methyl esters, by saponification. By the action of ammonia or amine on these esters there are formed asides. Further lung-I
- tonal groups have to be blocked temporarily, if no-Cicero, my protective groups, as they are common in peptize chemistry.
Furthermore, the finlike OH groups may also ye protected for example by acetylation during the aside synthesis. They are split off from the reaction product in known manner by a treatment with alkali, ammonia or amine. It is also possible, however, to prepare the aside bond without previous protection of the OH groups, if the condensation is carried out by way of carbodiimide in the presence of an additive, such as 1-hydroxybenzo-triazole (Chum. Ben. 103, (1970) pages 788 to 798).
2-Carboxy-carbonamide groups are prepared from the inner androids The finlike depot bodies to be used in accordance with the invention may partially be present as salts, for example alkali metal or alkaline earth metal salts, or as salts with organic bases, for example trishydroxy-methylaminomethane. These salts are obtained for example by dissolving or suspending the corresponding finlike compound in water and adding a base, while stirring, until a pi of from 7.0 to 7.5 is reached and main-twined.
. The secretion preparations of the invention are used for treating and preventing hemorrhages of the intestinal tract and for the treatment of ulcer, said preparations being administered by injection or rectally.
In the following Examples there have been indicated general directions which are easy to carry out for pro-Jo paring the depot bodies and depot preparations, how-ever, without restricting the invention.
E X A M P L E
. . . _ Components such as alkylamine, esters, left. amine or alkylamide mentioned in this Example contain up to 8 carbon atoms.
A. 1 Mow of an acetoxy-benzoic acid is boiled in S times the amount (g/v) of thinly chloride for a period of from 30 minutes to 1 hour. The excess thinly chloride is distilled off, then the batch is no-distilled with Tulane, and the residue is dissolved in Tulane, tetrahydrofuran, dim ethyl acetamide or other substances and combined with 2 mows of amine component (alkylamine, dialkylamine, morpholine, Tarzan ester or Tarzan alkylamide, Lawson ester or Lawson alkylamide, ~minoalkyl-phosphonic acid, aminoalkyl-dialkyl-phosphine oxide, aminobenzene sulfonamide and others) or with 1 mow of amine component and 1 mow of a tertiary amine, whereupon the mixture is allowed to react for 1 to 2 hours at room temperature, with stirring. For work-up, the reaction mixture is poured into water, the precipi-late is filtered off and purified by recrystalli-ration from methanol or other substances. If the come pound is too easily soluble in water, the solvent is distilled off, and the residue is digested with a small amount of water or ethanol. The product is purified by recrystallization from isopropanol, ethyl acetate, or similar substances.
In order to split the Aztecs groups and esters, if any, the product is saponified with 1.5 mows of ON Noah per cleavable group in methanol or methanol/
dioxan~water (about 3:3:1). It is neutralized after about 1 hour with Hal, the solvent is distilled off, US thereafter the product is taken up optionally sup-pension) in water and acidified with Hal. The prows-pirate is filtered off and washed with water. In the case of easily water-soiuble compounds, the solution of the compounds is diluted directly following the saponification with methanol/water (1:1), filtered via a strongly acid ion exchanger and evaporated to dryness. The residue is recrystallized from a suit-able solvent such as isopropanol, ethyl acetate, or similar substances.
B. 1 Mow of a hydroxy-benzoic acid and 1 mow of an amine component according to Example 1 are dissolved in dim ethyl formamide. There are added 1 mow of 1-hydroxy-benzotriazole and 1 mow of dicyclohexyl carbodiimide, and after 4 hours the solution is filtered off from the precipitated dicyclohexyl urea, thereafter a crude product is precipitated with petrol Lomb ether which may be purified by digesting with methanol or by recrystallization from methanol or isopropanol. Esters are optionally saponified accord ding to Example 1 A.
3,5-Dihydroxybenzoyl-L-tyrosine a. 3,5-DihYdroxYbenzoyl-L-tyrosine methyl ester 231.2 g of 3,5-dihydroxybenzoic acid are disk solved in 4 l of dim ethyl formamide. 313 g of L-tyrosine-methyl ester hydrochloride, 202 g of l-hydroxybenzotriazole and 346 ml of N-ethyl morn choline and subsequently 297 g of dicyclohexyl carbodiimide are added. The mixture is stirred over night at room temperature, and the precipi-toted dicyclohexyl urea is filtered off. The sol-vent is distilled off in vacua, the residue is taken up in 4 l of ethyl acetate, the ethyl acetate solution is washed 4 times each with say turated sodium hydro~enocarbona~e solution, 3 times with 400 ml each of a solution of 5 % KHS04 and K2S04 and twice with 200 ml each of water, dried over sodium sulfate and subsequently brought to dryness. Yield: 360 g of resin.
b. 3,5-Dihydroxybenzoyl-L-tyrosine The resin as obtained above is dissolved in about 1.4 1 of ON Noah, and the solution is ad-jutted to pi 12.5 with ON Noah. The reaction mixture is saponified under a nitrogen atmosphere and with pi control, while adding ON Noah and maintaining a constant pi of 12.5 (period: about 15 hours). The alkaline solution is extracted 4 times with 500 ml of n-butanol each. The aqueous phase is neutralized with ON Hal, treated for 10 minutes with active charcoal (50 g), filtered and further acidified, as long as an oil separates.
Said oil is taken up in 1 l of n-butanol, the aqueous phase being extracted again twice with 300 ml each of n-buLanol. The combined buttonhole phases are washed twice with 100 ml each of saturated sodium chloride solution and once with 150 ml of water, dried over sodium sulfate, filtered and freed from the solvent in awoke.
The remaining oil is dissolved in 600 ml of acetone. The solution is filtered and introduced drops into 8 l of chloroform, while stirring vigorously. The precipitate is collected, washed - with chloroform and dried in vacua Yield: 255 g of a slightly hydroscopic powder.
The compound and the dicyclohexylamine salt thereof met with decomposition.
NOAH, 0.5 HO : 326.3;
gala. C 58.89 H 4.94 N 4.29 found C 58.9 H 5.2 N 4.2 C. 1 Mow of a hydroxybenzoyl-tyrosine or -tyrosyl-tyros-ne prepared according to Examples 1 A or 1 B is reacted according to Example 1 B with one of the above-men-toned amine components. The work-up and the purify-cation are carried out as under 1 B. Carboxylic acid esters may be saponified according to Example 1 B, the carboxylic acids obtained may be reacted once again with an amine component according to Example 1 B.
A suspension of 0.5 to 1 g of secretion hydrochloride and 250 g of 3,5-dihydroxybenzoyl-L-tyrosine is homogeni-Zen at 40 to 60C in 480 g of suppository mass consisting of a partial glyceride or polyethylene glycol with a solidification point of from 30 to 50C in each case, and the product obtained is filled into suppository molds, while being still in the liquid or semi liquid state. The weight of a suppository is about 2 g.
Operations are the same as those described under Example 2, save for using only 0.05 g of secretion hydra-chloride.
The process is carried out according to Example 2 12C~4~
or 3, while using 250 g of the sodium salt of Dow-hydroxybenzoyl-L-tyrosine.
The process is carried out as has been described in Example 2, 3 or 4, save for using 1 g of secretion citrate and 1000 g of suppository mass.
. .
A mixture of 0.5 g of secretion citrate, 200 g of 3,5-dihydroxybenzoyl-L-tyrosine or one of the fishily-jackal acceptable salts thereof and 500 g of a partially hydrogenated vegetable oil, for example sesame oil, soybean oil, palm oil or cola oil, is homogenized, and 2.0 g each are filled into rectal capsules 1 Gram of secretion hydrochloride is incorporated into a mixture of 250 g of the sodium salt of Dow-hydroxybenzoyl-L-tyrosine and 500 g of fatty acid-1,2-propylene glycol ester, the resulting product is grant-fated and molded into suppository molds.
_ .
At about 50C, 0.5 g of secretion hydrochloride is dissolved, while stirring, in a solution of 110 g of gelatin and 90 g of glycerol in 300 ml of water, the resulting solution is then mixed with 200 g of iris-hydroxymethyl amino methane salt of 3,5-dihydroxybenzoyl-L-tyrosine, then the mixture is filled into suppository molds and is allowed to cool rapidly.
Operations are as described in Examples 2 to 8, save for using another finlike depot body with a corresponding amount by weight.
A solution is prepared, for example, of A. 30 g of bis-phloretin-sodium phosphate (obtained according to KIWI. 78, 147 558 g) in 300 ml of water B. 80 g of gelatin derivative in 500 ml of water C. 1 million CUT of secretion and 2 g of Nail in 100 ml of water.
The solutions A to C are purified and made up to 1.0 liter with water. They are filtered under sterile conditions, filled under septic conditions into ampules of 1 ml each and lyophilized.
The process is carried out as has been described in Example 10, however, only the two solutions A and B are combined and made up to 1 liter, whereupon the solution is filled into ampules of 1 ml and lyophilized. Solution C contains, besides 1 million CUT of secreting 20 g of Gleason and 2 g of gelatin derivative and is separately filled in the same manner into ampules of 1000 CUT each and lyophilized.
Prior to being used, the depot body is dissolved in 1 ml of water. The lyophilized secretion is taken up in this solution and injected.
_ 30 Grams of 4-hydroxyphenyl-methylsulfoxide are dissolved in a mixture of 200 ml of 1,2-propylene glycol and 200 ml of water, and the resulting solution is combined with the solution of 80 g of gelatin derivative in 500 ml of water. The mixture is made up with water to 1 liter, filtered under sterile conditions and filled into ampules of 1 ml each.
. This solution is used to absorb the secretion pro-pared according to Example OWE Upon dissolution of the ampule contents, injections may be made immediately.
30 Grams of phloretin are dissolved with the aid of ON Noah in 300 ml of water, and after filtration of the solution the compound is precipitated in a finely divided form by adjusting the pi to 7.0 to 7.4 with diluted Hal. By stirring for a shorter or prolonged period, the particle size may be modified and for example brought to an appropriate value (e.g. 15 to 35 I). The substance is then combined with the sterile solution of 80 g of gelatin derivative in 500 ml of water, the total volume is made up to 1 liter and filled into ampules of 1 ml each.
Prior to being used, the suspended depot body is I
homogeneously distributed in the solution by slight agitation. Thereupon a secretion prepared according to Example 11 is dissolved in the aqueous suspension, the solution is agitated for a short time and injected, 30 Grams of 2,4-dihydroxybenzoyl Tarzan are disk solved in a manner analogous to that of Example 12 in 200 ml of propylene glycol and 800 ml of water, filtered under sterile conditions and filled into ampules of 1 ml each. In order to be used, the secretion having been filled into ampules according to Example 11 is taken up in this solution and injected.
30 Grams of 2,4-dihydroxybenzoyl-L-tyrosine are dissolved in 800 ml of water, while adding ON Noah up to about pi 8.5. The solution is then adjusted to pi 7.4 with ON HC1, made up with water to 1.0 1, filtered, filled into ampules of 1 ml each and lyophilized. In order to be used, the ampule contents are taken up in 1 ml of water, and the secretion having been filled into ampules according to Example 11 is dissolved therein.
Operations are the same as in Examples 10 to 13, save for using only 15 g of a finlike depot body and optionally 40 g of a gelatin derivative.
Operations are the same as in Example 10 to 13, save for using 60 g of a depot body and optionally 80 g of a gelatin derivative.
Use is made of one of the phenols specified in the Table, the compound being employed in a manner analogous to that of Examples 10 to 15, depending on its volubility.
This application is a division of Canadian Patent Applique-lion Serial No. 353,855, filed June 12,1980.
3,5-Dihydroxybenzoic acid L 25 6.6 3,5-Dihydro~ybenzoic acid aside L 34 6.2 2,4-Dihydroxybenzoic acid-benzylamide L 64 6.8 Bis-(2,4-dihydroxybenzoyl-)-diamuno- B 69 6.5 ethanes Bis-(3,5-dihydroxybenzoyl)-diamino- A 79 6.1 ethanes Bis-(2-hydroxybenzoyl)-diaminoethane A 72 5.9 Bis-(2,4-dihydroxybenzoyl)-1,4-di- B 83 6.7 amino butane Bis-(3,5-dihydroxybenzoyl)-1,4- AHAB 85 7.4 diaminobutane Tris-(2-hydroxybenzoyl)-diethylene- B 62 8.1 . thiamine Tris-(3-hydroxybenzoyl)-diethylene- A 71 8.0 thiamine Tris-(4-hydroxybenzoyl)-diethylene- B 68 7.8 trim me Tris-(3,5-dihydroxybenzoyl-diethylene- A 79 8.6 Truman Tetra-(2-hydroxybenzoyl)-triethylene- A 91 OWE
tetramine Tetra-(3-hydroxybenzoyl-)triethylene- A 95 9.1 tetramine Tetra-`13,5-dih~drox~enzoyl)-tri- A 101 9.7 ethylene-tetr~nine Tetra-(2,6-dihydroxybenzoyl)-tri- B 78 8.1 ethylene-tetramine ~,6~4~
- g -- HOE 79/F 144 K
Depot body Prepare- % vs. Rot. Intensity lion control ox effect over 5 hours .. . _ . ...
2,8-Dihydroxy-3-naphthoyl-di- B 77 9.1 ethanol amine Tris-(2,8-dihydroxy-3-naphthoyl)- B 94 9.4 diethylene-triamine 1-Hydroxy-2-naphthoic acid-diethanol- AHAB 79 8.1 aside 1-Hydroxy-2-naphthoic acid-ethanol- AHAB 74 8.0 aside 2-Hydroxy-5-chloro-benzoic acid- A 77 7.3 diethanolamide Bis-(3,5-dihydroxyben2oyl)-cys~amine AHAB 79 By 3-~2-Hydroxybenzoylamino)-benzene- A 81 8.1 sulfonamide Tetra-(3,5-dihydroxybenzoyl-L- A 98 OWE
tyrosyl)-triethylene-tetramine 3,5-Dihydroxybenzoyl-aminomethyl- A 75 8.9 phosphoric acid 2,4-Dihydroxyb~nzoyl-aminomethvl~ B 79 8.6 dimethylphosph me oxide 2,4-Dihydroxybenzoyl-L-tyrosine- B 70 7 . 8 ethyl ester N No ~-Bis(3,5-dihydroxybenzoyl-L- C 86 8.8 tyrosyl)-L-lysine-diethanol-amide Ben~-loxycarbonyl-L-tyrosine L 7 5.9 3,5-Dihydroxybenzoyl-L-tyrosine B 76 9.2 2,4-Dihydroxybenzoyl-L-tyrosine B 84 10.5 2,4-Dihydrox~-benzoyl-L-tyrosine-n- C 87 8.7 butylamide 3,5-Dihydroxybenzoyl-L-tyrosine-di- C 76 7.6 ethanolamide 2,4-Dihydroxykenzoyl-L,tyrosine-di- C 47 8.7 ethanolamide Bis-(benzylo~carbonyl-L-~y.rosine)- C 44 SO
diaminoethane 12~4~4~
Depot body Prepare- I% vs. Rel.Int~sity lion control of effect o'er S his . _ . . . .
Bis-(3,5-dihydroxy~enzoyl-L-tyrosine)- C 58 7.0 diaminoethane Bis-(2~bcxybenzoyl-L-tyrosine)- C - 48 6.3 diaminoethane Bis-(2,4~hydroxybenzoyl-L,tyrosine)- C 82 6.0 diaminoethane Bis-~3-benzoylpropionyl-L-tyrosine)- C 60 3.7 diaminoethane Eenzyloxycarbonyl-L-tyrosyl-L-ty~o- L 62 7.5 sine No -Bis-(benzyloxycar~onyl-Lr C 48 7.0 tyrosyl)-L-lysine N No -Bis-(benzyloxycarbonyl-L- C 13 1.5 tyrosyl)-D-lysine N No -Bis-(benzyloxycarbonyl-L- C 93 8.2 tyrosyl)-L-lysine-methyl ester NUN -Bis-(benzyloxycarbonyl-L- C 90 8.4 tyrosyl)-L-lysine-amide As may be seen from the Tables, all finlike depot bodies tested have a protracting and intensifying in-fluency on the secreting The depot bodies which may be employed according to the invention are either compounds known from literature or those wish are prepared for example in accordance with the methods described in the experimental part. It is a great advantage that even low-molecular compounds of simple structure which may easily be obtained are suitable depot bodies.
The fact that these finlike depot bodies are not only present in admixture with secreting but also form addition products with the latter, may easily be seen from the drastic reduction of the molecular extinction of the phenols in the proximity of 280 no by up to 50 %, 1~44~
while adding increasing amounts of secreting however, since the said adduce formation is fever-sidle and subject to the law of mass action, it is ad-vintages to use a large molar excess of depot bodies.
For the subcutaneous administration in humans, from 10 to 100 my of a depot body in 1 to 2 ml of solution or suspension are used per 80 to 1000 clinical units (CUT; 1 my of secretion = 4000 CUT according to Gut 19 (1978, page 355~, 1 my of secretion is reported to have a biological effect corresponding to 5000 CUT). If a gelatin derivative is added to improve the effect, its concentration is from 30 to 100 mg/ml. Also the gelatin derivatives optionally present in the secretion reduce the US extinction of the phenols and are thus present in a complex bond. For preparing the adduces and mix-uses it is sufficient to bring the components into contact with one another for a short time in a solution. The adduce formation takes place rapidly.
As finlike depot bodies for the rectally ad mini-storable secretion preparations there may also be used those specified in the Table.
It is a great advantage also for this type of pro-parathion that already low-molecular compounds of simple structure which are easily accessible are suitable to increase the available amount of secretion from suppose-tories or rectal capsules in a way that a rectal apply-cation of secretion becomes possible or useful for the first time. The reversible adduce formation mentioned before also takes place, and it is equally advantageous to use a large molar excess of depot bodies.
The intensified effect of secretion in the form of rectally administrable preparations due to the depot bodies used according to the invention becomes evident from the drawing. In a test carried out on 8 rats each weighing 0.5 kg, 100 go of secretion in a suppository of a weight of 73 my cause the production of 92 Al of pancreatic juice (curve 1). With the addition of 25 my of 3,5-dihydroxybenzoyl-L-tyrosine the volume of pane-retook juice rose to 1778 Al (curve 2). This corresponds 4~48 to an increase of the effect to about 20 times its original value. Besides, a protracted action can also be observed. In the present case the secretion dose has been chosen very high, in order to obtain a measurable Sol-use also without additive.
With a non-maximum stimulation in the normal dose range (about half the dose), the increase of the effect is about 50-fold.
For the treatment of humans, from about 0.1 to 2 my of secretion are required per suppository (= 400 to 8000 clinical units CUT 1 my of secretion = 4000 CUT according to Gut 19 (1978), page 355, 1 my of secretion is stated to have a biological effect corresponding to 5000 CUT).
The minimum amount of depot bodies is about 50 my. The maximum amount is determined by the processibility. For a suppository of a weight of about 2 g it is up to 1 to 1.5 g, Another subject of the invention is a process for the manufacture of a secretion preparation having a pro-treated and intensified action.
A subcutaneously administrable preparation of the invention is preferably obtained by dissolving secretion hydrochloride prepared according to US Patent No.
4,098,779 (corresponding to German Offenlegungsschrift No. 2,615,229) in water or in the aqueous solution of one of the above-specified gelatin derivatives and come brining the resulting solution with the solution of the depot body in water. In this process the pi value is in the range of from 7 to 8.5. It is adjusted to 7.0 to 7.8 with a physiologically acceptable acid, whereupon the solution is lyophilized.
Some depot bodies are sparingly soluble and are - present under the above conditions in a suspension. In this case an amorphous or crystalline suspension is pro-us pared by precipitation of the phenols dissolved at pi 10 and adjustment of the pi to the range between 7.0 and 7.4, which suspension may be stabilized by the presence of a gelatin derivative as defined above. This suspension is combined with the aqueous solution of secreting or I
- 13 - HOE 79/F 1~4 X
lyophilized secretion is dissolved in this aqueous suspension. Already after a short time the secretion has been fully adsorbed to the depot body. This secreting containing suspension should be injected within one week.
Furthermore, it is also possible to dissolve the finlike depot bodies in water containing up to 30 % of a solubilizer. Suitable solubilizers are 1,2-propylene glycol, battalion glyc~l, polyethylene glycol, twitter-hydrofurfuryl alcohol-polyethylene glycol ether, dim ethyl sulfoxide, N-methyl pyrrolidone or dim ethyl formamide.
In this case the solution of the depot carrier is prefer-ably prepared without secreting and said solution which is not lyophilized is filled into ampules of preferably 1 to 2 ml. In a second ampule the secretion is present in a lyophilized state. Immediately prior to application the secretion is dissolved in the solution of the depot carrier, whereupon the adduce is formed. A gelatin don-votive may optionally be added to the secretion or the depot body or both.
The process for the manufacture of rectally ad mini-storable secretion preparations with protracted and intent silted action comprises preparing suppositories or rectal capsules from a mixture of a generally common carrier, secretion and a phènolic depot body as kirk-terraced above.
As suppository mass there are used known compounds, for example partial glycerides, i.e. mixtures of moo-and divesters of glycerol with higher fatty acids, further-more fatty acid-1,2-propylene-glycol esters, and more-over polyethylene glycols with a solidification range of from about 30 to 50C. The secretion suspension in-corporate into masses of this kind or into oil, to-getter with the phenols to be used according to the invention, may also be filled off into commercial rectal capsules.
The suppositories are manufactured by homogenizing the mixture of carrier, secretion and a phenol to be used according to the invention in the melt and subset 41~3 quaintly filling it into suppository molds, while being still in the liquid state, in which molds said mixture is allowed to solidify. Semisolid or oily suspensions are filled into rectal capsules. The weight of a suppository is from about 1 to 3 g.
In a similar manner it is also possible to menu-lecture suppositories on the basis of glycerol and gelatin.
Suppository masses such as fatty acid-1,2-propylene glycol ester are mixed together with secretion and a depot body to be used according to the invention and molded into granules without melting. The suppositories or rectal capsules of the invention are used for treating and preventing hemorrhages of the intestinal tract and for the treatment of ulcer. They represent the first secretion preparation not to be administered any longer by injection The invention relates further to the finlike compounds specified in the Table which have not yet been described in literature, which may be prepared according to the processes indicated above and are used as depot bodies for the secretion preparations of the invention. A special subject of this invention is 3,5-dihydroxybenzoyl-L-tyrosine.
Finlike depot bodies with carbonamide groups are synthesized according to common methods for the prepare-lion of carbonamide compounds, if they have not been known from literature.
Particularly suitable and easily accessible depot bodies, as they are specified in the Table, may by pro-pared for example from hydroxyl group-~arrying car boxy-fig acids and amine. Amine components may also be amine optionally carrying hydroxyl groups, amino acid esters, peptize esters or amino acid- or peptize asides.
If the amine components contain carboxylic acid groups, the latter are advantageously prepared from the corresponding esters, in most cases methyl esters, by saponification. By the action of ammonia or amine on these esters there are formed asides. Further lung-I
- tonal groups have to be blocked temporarily, if no-Cicero, my protective groups, as they are common in peptize chemistry.
Furthermore, the finlike OH groups may also ye protected for example by acetylation during the aside synthesis. They are split off from the reaction product in known manner by a treatment with alkali, ammonia or amine. It is also possible, however, to prepare the aside bond without previous protection of the OH groups, if the condensation is carried out by way of carbodiimide in the presence of an additive, such as 1-hydroxybenzo-triazole (Chum. Ben. 103, (1970) pages 788 to 798).
2-Carboxy-carbonamide groups are prepared from the inner androids The finlike depot bodies to be used in accordance with the invention may partially be present as salts, for example alkali metal or alkaline earth metal salts, or as salts with organic bases, for example trishydroxy-methylaminomethane. These salts are obtained for example by dissolving or suspending the corresponding finlike compound in water and adding a base, while stirring, until a pi of from 7.0 to 7.5 is reached and main-twined.
. The secretion preparations of the invention are used for treating and preventing hemorrhages of the intestinal tract and for the treatment of ulcer, said preparations being administered by injection or rectally.
In the following Examples there have been indicated general directions which are easy to carry out for pro-Jo paring the depot bodies and depot preparations, how-ever, without restricting the invention.
E X A M P L E
. . . _ Components such as alkylamine, esters, left. amine or alkylamide mentioned in this Example contain up to 8 carbon atoms.
A. 1 Mow of an acetoxy-benzoic acid is boiled in S times the amount (g/v) of thinly chloride for a period of from 30 minutes to 1 hour. The excess thinly chloride is distilled off, then the batch is no-distilled with Tulane, and the residue is dissolved in Tulane, tetrahydrofuran, dim ethyl acetamide or other substances and combined with 2 mows of amine component (alkylamine, dialkylamine, morpholine, Tarzan ester or Tarzan alkylamide, Lawson ester or Lawson alkylamide, ~minoalkyl-phosphonic acid, aminoalkyl-dialkyl-phosphine oxide, aminobenzene sulfonamide and others) or with 1 mow of amine component and 1 mow of a tertiary amine, whereupon the mixture is allowed to react for 1 to 2 hours at room temperature, with stirring. For work-up, the reaction mixture is poured into water, the precipi-late is filtered off and purified by recrystalli-ration from methanol or other substances. If the come pound is too easily soluble in water, the solvent is distilled off, and the residue is digested with a small amount of water or ethanol. The product is purified by recrystallization from isopropanol, ethyl acetate, or similar substances.
In order to split the Aztecs groups and esters, if any, the product is saponified with 1.5 mows of ON Noah per cleavable group in methanol or methanol/
dioxan~water (about 3:3:1). It is neutralized after about 1 hour with Hal, the solvent is distilled off, US thereafter the product is taken up optionally sup-pension) in water and acidified with Hal. The prows-pirate is filtered off and washed with water. In the case of easily water-soiuble compounds, the solution of the compounds is diluted directly following the saponification with methanol/water (1:1), filtered via a strongly acid ion exchanger and evaporated to dryness. The residue is recrystallized from a suit-able solvent such as isopropanol, ethyl acetate, or similar substances.
B. 1 Mow of a hydroxy-benzoic acid and 1 mow of an amine component according to Example 1 are dissolved in dim ethyl formamide. There are added 1 mow of 1-hydroxy-benzotriazole and 1 mow of dicyclohexyl carbodiimide, and after 4 hours the solution is filtered off from the precipitated dicyclohexyl urea, thereafter a crude product is precipitated with petrol Lomb ether which may be purified by digesting with methanol or by recrystallization from methanol or isopropanol. Esters are optionally saponified accord ding to Example 1 A.
3,5-Dihydroxybenzoyl-L-tyrosine a. 3,5-DihYdroxYbenzoyl-L-tyrosine methyl ester 231.2 g of 3,5-dihydroxybenzoic acid are disk solved in 4 l of dim ethyl formamide. 313 g of L-tyrosine-methyl ester hydrochloride, 202 g of l-hydroxybenzotriazole and 346 ml of N-ethyl morn choline and subsequently 297 g of dicyclohexyl carbodiimide are added. The mixture is stirred over night at room temperature, and the precipi-toted dicyclohexyl urea is filtered off. The sol-vent is distilled off in vacua, the residue is taken up in 4 l of ethyl acetate, the ethyl acetate solution is washed 4 times each with say turated sodium hydro~enocarbona~e solution, 3 times with 400 ml each of a solution of 5 % KHS04 and K2S04 and twice with 200 ml each of water, dried over sodium sulfate and subsequently brought to dryness. Yield: 360 g of resin.
b. 3,5-Dihydroxybenzoyl-L-tyrosine The resin as obtained above is dissolved in about 1.4 1 of ON Noah, and the solution is ad-jutted to pi 12.5 with ON Noah. The reaction mixture is saponified under a nitrogen atmosphere and with pi control, while adding ON Noah and maintaining a constant pi of 12.5 (period: about 15 hours). The alkaline solution is extracted 4 times with 500 ml of n-butanol each. The aqueous phase is neutralized with ON Hal, treated for 10 minutes with active charcoal (50 g), filtered and further acidified, as long as an oil separates.
Said oil is taken up in 1 l of n-butanol, the aqueous phase being extracted again twice with 300 ml each of n-buLanol. The combined buttonhole phases are washed twice with 100 ml each of saturated sodium chloride solution and once with 150 ml of water, dried over sodium sulfate, filtered and freed from the solvent in awoke.
The remaining oil is dissolved in 600 ml of acetone. The solution is filtered and introduced drops into 8 l of chloroform, while stirring vigorously. The precipitate is collected, washed - with chloroform and dried in vacua Yield: 255 g of a slightly hydroscopic powder.
The compound and the dicyclohexylamine salt thereof met with decomposition.
NOAH, 0.5 HO : 326.3;
gala. C 58.89 H 4.94 N 4.29 found C 58.9 H 5.2 N 4.2 C. 1 Mow of a hydroxybenzoyl-tyrosine or -tyrosyl-tyros-ne prepared according to Examples 1 A or 1 B is reacted according to Example 1 B with one of the above-men-toned amine components. The work-up and the purify-cation are carried out as under 1 B. Carboxylic acid esters may be saponified according to Example 1 B, the carboxylic acids obtained may be reacted once again with an amine component according to Example 1 B.
A suspension of 0.5 to 1 g of secretion hydrochloride and 250 g of 3,5-dihydroxybenzoyl-L-tyrosine is homogeni-Zen at 40 to 60C in 480 g of suppository mass consisting of a partial glyceride or polyethylene glycol with a solidification point of from 30 to 50C in each case, and the product obtained is filled into suppository molds, while being still in the liquid or semi liquid state. The weight of a suppository is about 2 g.
Operations are the same as those described under Example 2, save for using only 0.05 g of secretion hydra-chloride.
The process is carried out according to Example 2 12C~4~
or 3, while using 250 g of the sodium salt of Dow-hydroxybenzoyl-L-tyrosine.
The process is carried out as has been described in Example 2, 3 or 4, save for using 1 g of secretion citrate and 1000 g of suppository mass.
. .
A mixture of 0.5 g of secretion citrate, 200 g of 3,5-dihydroxybenzoyl-L-tyrosine or one of the fishily-jackal acceptable salts thereof and 500 g of a partially hydrogenated vegetable oil, for example sesame oil, soybean oil, palm oil or cola oil, is homogenized, and 2.0 g each are filled into rectal capsules 1 Gram of secretion hydrochloride is incorporated into a mixture of 250 g of the sodium salt of Dow-hydroxybenzoyl-L-tyrosine and 500 g of fatty acid-1,2-propylene glycol ester, the resulting product is grant-fated and molded into suppository molds.
_ .
At about 50C, 0.5 g of secretion hydrochloride is dissolved, while stirring, in a solution of 110 g of gelatin and 90 g of glycerol in 300 ml of water, the resulting solution is then mixed with 200 g of iris-hydroxymethyl amino methane salt of 3,5-dihydroxybenzoyl-L-tyrosine, then the mixture is filled into suppository molds and is allowed to cool rapidly.
Operations are as described in Examples 2 to 8, save for using another finlike depot body with a corresponding amount by weight.
A solution is prepared, for example, of A. 30 g of bis-phloretin-sodium phosphate (obtained according to KIWI. 78, 147 558 g) in 300 ml of water B. 80 g of gelatin derivative in 500 ml of water C. 1 million CUT of secretion and 2 g of Nail in 100 ml of water.
The solutions A to C are purified and made up to 1.0 liter with water. They are filtered under sterile conditions, filled under septic conditions into ampules of 1 ml each and lyophilized.
The process is carried out as has been described in Example 10, however, only the two solutions A and B are combined and made up to 1 liter, whereupon the solution is filled into ampules of 1 ml and lyophilized. Solution C contains, besides 1 million CUT of secreting 20 g of Gleason and 2 g of gelatin derivative and is separately filled in the same manner into ampules of 1000 CUT each and lyophilized.
Prior to being used, the depot body is dissolved in 1 ml of water. The lyophilized secretion is taken up in this solution and injected.
_ 30 Grams of 4-hydroxyphenyl-methylsulfoxide are dissolved in a mixture of 200 ml of 1,2-propylene glycol and 200 ml of water, and the resulting solution is combined with the solution of 80 g of gelatin derivative in 500 ml of water. The mixture is made up with water to 1 liter, filtered under sterile conditions and filled into ampules of 1 ml each.
. This solution is used to absorb the secretion pro-pared according to Example OWE Upon dissolution of the ampule contents, injections may be made immediately.
30 Grams of phloretin are dissolved with the aid of ON Noah in 300 ml of water, and after filtration of the solution the compound is precipitated in a finely divided form by adjusting the pi to 7.0 to 7.4 with diluted Hal. By stirring for a shorter or prolonged period, the particle size may be modified and for example brought to an appropriate value (e.g. 15 to 35 I). The substance is then combined with the sterile solution of 80 g of gelatin derivative in 500 ml of water, the total volume is made up to 1 liter and filled into ampules of 1 ml each.
Prior to being used, the suspended depot body is I
homogeneously distributed in the solution by slight agitation. Thereupon a secretion prepared according to Example 11 is dissolved in the aqueous suspension, the solution is agitated for a short time and injected, 30 Grams of 2,4-dihydroxybenzoyl Tarzan are disk solved in a manner analogous to that of Example 12 in 200 ml of propylene glycol and 800 ml of water, filtered under sterile conditions and filled into ampules of 1 ml each. In order to be used, the secretion having been filled into ampules according to Example 11 is taken up in this solution and injected.
30 Grams of 2,4-dihydroxybenzoyl-L-tyrosine are dissolved in 800 ml of water, while adding ON Noah up to about pi 8.5. The solution is then adjusted to pi 7.4 with ON HC1, made up with water to 1.0 1, filtered, filled into ampules of 1 ml each and lyophilized. In order to be used, the ampule contents are taken up in 1 ml of water, and the secretion having been filled into ampules according to Example 11 is dissolved therein.
Operations are the same as in Examples 10 to 13, save for using only 15 g of a finlike depot body and optionally 40 g of a gelatin derivative.
Operations are the same as in Example 10 to 13, save for using 60 g of a depot body and optionally 80 g of a gelatin derivative.
Use is made of one of the phenols specified in the Table, the compound being employed in a manner analogous to that of Examples 10 to 15, depending on its volubility.
This application is a division of Canadian Patent Applique-lion Serial No. 353,855, filed June 12,1980.
Claims (4)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a dihydroxybenzoyl-L-tyrosine in which a dihydroxybenzoic acid is reacted with an acid addition salt of an L-tyrosine-alkylester in the presence of an amine, the resultant dihydroxybenzoyl-L-tyrosine-alkylester is hydrolyzed in an alkaline medium and the dihydroxybenzoyl-L-tyrosine is isolated.
2. A dihydroxybenzoyl-L-tyrosine, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.
3. A process for the preparation of 3,5-dihydroxybenzoyl-L-tyrosine in which 3,5-dihydroxybenzoic acid is reacted with an acid addition salt of L-tyrosine-methylester in the presence of an amine, the resultant 3,5-dihydroxybenzoyl-L-tyrosine-methyl-ester is hydrolyzed in an alkaline medium and 3,5-dihydroxybenzoyl-L-tyrosine is isolated.
4. 3,5-Dihydroxybenzoyl-L-tyrosine, whenever obtained according to a process as claimed in claim 3 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000416529A CA1204448A (en) | 1979-06-13 | 1982-11-26 | Secretin preparations with intensified and protracted action, process for their manufacture, their use as well as dihydroxy-benzoyl-l-tyrosine |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP2923878.6 | 1979-06-13 | ||
| DE19792923878 DE2923878A1 (en) | 1979-06-13 | 1979-06-13 | Prolonged action secretin injectable preparations - for intestinal haemorrhage and ulcer treatment contg. a phenolic cpd. with depot effect e.g. a hydroxybenzoic acid deriv. |
| DE19803013105 DE3013105A1 (en) | 1980-04-03 | 1980-04-03 | Secretin compsn. contg. phenol deriv. - to enhance and prolong activity, useful for treating ulcers and intestinal bleeding |
| DEP3013105.6 | 1980-04-03 | ||
| CA000353855A CA1161755A (en) | 1979-06-13 | 1980-06-12 | Secretin preparations with intensified and protracted action, process for their manufacture, their use as well as dihydroxy-benzoyl-tyrosine |
| CA000416529A CA1204448A (en) | 1979-06-13 | 1982-11-26 | Secretin preparations with intensified and protracted action, process for their manufacture, their use as well as dihydroxy-benzoyl-l-tyrosine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1204448A true CA1204448A (en) | 1986-05-13 |
Family
ID=27166710
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000416529A Expired CA1204448A (en) | 1979-06-13 | 1982-11-26 | Secretin preparations with intensified and protracted action, process for their manufacture, their use as well as dihydroxy-benzoyl-l-tyrosine |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1204448A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114774395A (en) * | 2022-06-02 | 2022-07-22 | 亿彤科技发展(福建)有限公司 | High-purity chitinase 3-like protein 1 epitope peptide for liver disease detection and preparation method thereof |
-
1982
- 1982-11-26 CA CA000416529A patent/CA1204448A/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114774395A (en) * | 2022-06-02 | 2022-07-22 | 亿彤科技发展(福建)有限公司 | High-purity chitinase 3-like protein 1 epitope peptide for liver disease detection and preparation method thereof |
| CN114774395B (en) * | 2022-06-02 | 2023-08-22 | 亿彤科技发展(福建)有限公司 | High-purity chitinase 3-like protein 1 epitope peptide for liver disease detection and preparation method thereof |
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