CA1177401A - Method of using motility increasing peptides - Google Patents
Method of using motility increasing peptidesInfo
- Publication number
- CA1177401A CA1177401A CA000362430A CA362430A CA1177401A CA 1177401 A CA1177401 A CA 1177401A CA 000362430 A CA000362430 A CA 000362430A CA 362430 A CA362430 A CA 362430A CA 1177401 A CA1177401 A CA 1177401A
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- CA
- Canada
- Prior art keywords
- denotes
- carbon atoms
- alkyl
- alpha
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
Abstract
Abstract of the Disclosure Peptides of the formula A - Tyr - B - C - D - E
wherein A denotes hydrogen, alkyl, alkenyl, or alkenyleycloalkyl, each having up to 7 carbon atoms, an .alpha.-amino acid or a peptide with 2 or 3 amino acids, B denotes an .alpha.-amino acid or .alpha.-amino-isobutyric acid, C denotes glycine or azaglycine, D denotes phenylalanine which can be substituted in the benzene nucleus by methyl, methoxy, halogen, nitro or trifluoromethyl; dehydro- or hexahydrophenylalanine;
aza- or N-methylphenylalanine, and E denotes (a) -O-R1 or wherein, R1, R2 and R3 are identical or different and are hydrogen, alkyl with 1 to 6 carbon atoms;
cycloalkyl with 3 to 6 carbon atoms; alkenylcycloalkyl with 4 to 8 carbon atoms; hydroxyalkyl or dihydroxy-alkyl, thio alkyl or mercaptoalkyl with 1 to 6 carbon atoms; aryl with 6 to 10 carbon atoms; aralkyl with 7 to 11 carbon atoms, or R2 and R3 together denote poly-methylene with 2 to 6 carbon atoms, or Rl denotes methyl-polyethylene glycol having a degree of poly-merization of up to about 50, (b) an amino alcohol or an amino acid, which on its part may carry one of the groups defined sub (a); or (c) homoserine or homocysteine thiolactone in association with a pharmaceutically acceptable carrier: with the proviso that peptides of the formula H-Tyr X-Gly-Phe-Met-Y, wherein X denotes D-Ala, D-Leu, D-He, D-Val, D-Phe, D-Tyr, D-Trp, D-Ser, D-Thr, D-Met, D-Glu, D-Gln, D-Asp, D-Asn, D-Lys, or D-Arg and Y denotes NH2 or OH are excluded. These compounds stimulate the motility of the muscles of the gastro-intestinal tract and, therefore, they can be used for treating paralytic symptoms of these organs.
wherein A denotes hydrogen, alkyl, alkenyl, or alkenyleycloalkyl, each having up to 7 carbon atoms, an .alpha.-amino acid or a peptide with 2 or 3 amino acids, B denotes an .alpha.-amino acid or .alpha.-amino-isobutyric acid, C denotes glycine or azaglycine, D denotes phenylalanine which can be substituted in the benzene nucleus by methyl, methoxy, halogen, nitro or trifluoromethyl; dehydro- or hexahydrophenylalanine;
aza- or N-methylphenylalanine, and E denotes (a) -O-R1 or wherein, R1, R2 and R3 are identical or different and are hydrogen, alkyl with 1 to 6 carbon atoms;
cycloalkyl with 3 to 6 carbon atoms; alkenylcycloalkyl with 4 to 8 carbon atoms; hydroxyalkyl or dihydroxy-alkyl, thio alkyl or mercaptoalkyl with 1 to 6 carbon atoms; aryl with 6 to 10 carbon atoms; aralkyl with 7 to 11 carbon atoms, or R2 and R3 together denote poly-methylene with 2 to 6 carbon atoms, or Rl denotes methyl-polyethylene glycol having a degree of poly-merization of up to about 50, (b) an amino alcohol or an amino acid, which on its part may carry one of the groups defined sub (a); or (c) homoserine or homocysteine thiolactone in association with a pharmaceutically acceptable carrier: with the proviso that peptides of the formula H-Tyr X-Gly-Phe-Met-Y, wherein X denotes D-Ala, D-Leu, D-He, D-Val, D-Phe, D-Tyr, D-Trp, D-Ser, D-Thr, D-Met, D-Glu, D-Gln, D-Asp, D-Asn, D-Lys, or D-Arg and Y denotes NH2 or OH are excluded. These compounds stimulate the motility of the muscles of the gastro-intestinal tract and, therefore, they can be used for treating paralytic symptoms of these organs.
Description
~77q~a~L
- 2 - HOE 79/F ~78 lt~ has ],eell found that peptides of the formula :[
7~ - '.ryl -- B -- C -~ D - E
sti.mulate the motility of the museles o.~ the yastro-intestinal trae~. and, therefore, they ean k,e usecl ~or treating paralytie symptoms of these organs.
In the above formula A denotes hydrogen, alkyl, alkenyl, or alkenylcycloalkyl eaeh having up to 7 earbon atoms, an ~ -amino aci.d or a peptide with 2 or 3 amino aeids, preferably of the l~configuration, B denotes a d-amino acid or ;~-amino-isobutytric acid, C deno-tes glycine or azaglycine, D denotes phenylalanine which can be substituted in the benzene nueleus by methyl, methoxy, halogen, nitro or trifluoromethyl; dehydro- or hexahydrophenylalanine;
aza- or N-methylphenylalanine, and E denotes / R2 (a) -O-R1 or -N
in whieh R1, R2 and R3 are identieal or different and are hydrogen, alkyl with 1 -to 6 earbon atoms; eyelo-alkyl with 3 to 6 earbon atoms; alkenyleyeloalkyl with 4 to 8 earbon atoms; hydroxyalkyl or dihydroxyalkyl, thio alkyl or mereaptoalkyl with 1 to 6 earbon atoms;
aryl ~ith 6 to 10 carbon atoms; aralkyl with 7 to 11 earbon atoms, or R2 and R3 together denote polymethylene with 2 to 6 earbon atoms, or R1 denotes methyl-poly-e~hylene glyeol having a degree of polymerization of up to about 50, (b) an amino aleohol or an amino aeid, whieh on its part, may carry one of the groups deiined sub (a); or (e) homoserine or homocysteine thiolactone.
Important aceumulations of liquid and gas as a result o lae~ing spontaneous motillty of the ileum are a eharacteristic of post-operative intestinai atony.
They may hinder the s--.art of spontaneous motoricity by o~erstretchirly o:E t:he intestinal wall. ~s a further eonsequenee eLeetrolytes ancl liquids may exuclate i.nto ~L~7~40~L
- - 3 - HOE 79/F _ 7 the lumerl of the bowels resulting in cir:culatory brea~ dC?~ I d3n~jerous to life. This development is counteracted b~ the peptides of the invention.
The peptides of the invention stimulate the motoricity of the gastro-intestinal tract and the efferen-t urinary tract in dogs and men. They increase the restin~ tonus and the se~mental contraction activity of the intestines and, therefore, promote secondly the water resorption from the lumen of the bowels ti1eum).
They have also a motility increasing action on the muscles of the efferent urinary tract and, therefore, they are suitable to stop atonies of the gastro-intesti-nal tract and of the efferent urinary tract.
~his effect is surprising, the more so as the peptides according to the invention are, in principle, known from literature. They have been tested as to their morphium-like action as enkephaline analoys in the ileum of Guinea pigs of which they hinder the contrac-tion. It has not been realized, however, that this effect is reversed in some species; whereby these compounds become valuable medicaments.
Up to now, attempts have been made to remedy post-operative intestinal atonies, characterized by the lack of the spontaneous motility of the intestine, by ad-ministration of parasympathomimetics. But a treatment of this type involves the danger of undesired systemic cholinergic effect, which is not the case with the peptldes to be used according to the invention.
It is therefore, the object of the present invention to provide a method of usiny peptides of the formula I
for increasing the motility of the muscles of the gastro-intestinal tract and the urinary tract and treating paralytic symptoms of -these muscles.
Suitable amino acids for component A in the formula I are preferably amino acids occurr:ing in proteins and the simple metabolites thereof, such as ornithine, methionine sulfoxide or sulfone, homocysteine, or .; pyroglutamic acid.
o~ ~
- 4 - HOE 79/F_27~
Suitab:Le ~-d-amino acids for colriponent ~ in the formula I are preferably enantiomers of amino acid~
oecurring in nature, which may be substituted in the side chain. The amino yroup can be substitutea, for example, by alkanoyl, cycloalkanoyl, aroyl, or aralkanoyl ea~h having up to 10 carbon atoms, by alkyl-, cyclo-alkyl or aralkyl-oxycarbonyl each having up to 7 carbon atoms. Hydroxy groups or mercapto groups can oe etherified by alkyl, aryl or aralkyl each having up to 10 carbon atoms, and carboxy groups may carry the groupings defined sub E (a). Thioethers can be converted to sulfoxide or sulfone and aromatics can be substituted by halogen, methyl, methoxy, nitro, or 1:rifluoromethyl.
Another suitable ~-d-amino acid is norleucine.
The ~ -amino alcohols and ~i~-amino acids speci-fied sub E can be in the l~ or also d-configuration.
Their side chains can be subs-tituted as specified above for the amino acids mentioned sub B. Suitable amino alcohols are, in the first place, the reduction products -of the corresponding natural amino acids, for example prolinol or methioninol, which on its part may also be present as sulfoxide or sulfone.
Espccially good results are obtained with compounds in which component E is a methyl-polyethylene glycol having a degree of polymerization of up to 50. Compounds of this type are novel and are also a subject of the present invention.
They have the interesting property of increasing the effect of the basic peptide compound and to improve its solubility so that they make it possible to use the peptides, whieh are difficulty soluble for themselves, for the method of the invention.
Numerous representàtives of the peptides aecordiny to the invention are known from literature. In general, they are prepared by methods of peptide chemistr~ which are described in detail in a great number of publieations.
The peptides according to the invention are effective even :in a dose of 10 nanograms per kilogram althotlc3h no - adverse effeets are observed if they are adminl7texed in . ~ . ' , :
, .
~ 5 -- ~IOE 7g/F 278 higher doses. Uncler suitable conditions mor-phi.ne exhi-bits simi]ar effect, but only in an about 50 times highe-r~ dose. To obtain the same effect with carbaminoyl choline having a parasympathomimetric activity an about 10-fold dose in necessary. ~ence, the peptides according to the invention belong to the most active effectors of the motoricity of the gas'~ro-intestinal tract and the efferent urinary tract. It is known that they have a morphine-like effect bwt with the small doses required the hemato-encephalic barrier is not passed over after intravenous, subcutaneous or intra-nasal administration of the effective doses. Hence, in the amounts re~uired for the purposes of the invention they do not exhibit any effect in the central nervous system.
Variations of components A to D of the peptides do not change the quality of the described effect, they only result in a varying quantitative increase of the e~ffect as compared with the very weakly effective basic compound, i.e. natural enkephaline.
Depending on the compound used, doses of from 0.5 to 500 micrograms are given for men by intravenous administration or subcutaneous administration, whereas the dose for intranasal administration ranges from about 20 micrograms to 25 milligrams. In the case of resorption troubles, for example, the dose can be increased.
The compounds of the invention can be used for the treatment of post-operative atonies of the gastro-intestinal -tract and the efferent urinary tract They can also be used in the treatment of the Hirschsprung disease caused by an inherent megacolon. A therapy with the compounds of the invention has the advantage that the effect of the peptides can be counteracted at any time by administration of opiate antagonists.
The following e~amples illustrate the invention, they describe a characteristic syntllesis of a peptide according to the invention and the manufacture of pharrna-.
7 ~ 4 0 ~
~ 6 - HOE 79/F_278 eeutical preparatJons of pep-tides for their usc aecordirlg to -the iI~vention.
E X A M P l E
. . . _ r--D-L~s(For) G_~-Phe-Met~O-PEG3000-OMe a) Boc-Me -O-P~G3000 OM,e ~.0 g o commercia] polyethylerle glycol monomethyl ether having an average molecu]ar weight of 3,000 (PEG3 0OO-OMe) and 5.0 g of Boc~Met-O'H are dissolved in 50 ml of dimethyl formamide while gently heating. Ater 10 addition oE 2.0 g of 1-hydroxybenzotriazole and 4.5 g of dieyelohexyl earbodiimide, the mixture is left to stand for ~2 hours at room temperature. The reaction produet is then precipitated with ether and the preeipi-tation is repeated with ether from methylene chloride.
Yield 3.5 g.
b) II-Met O-PEG3000-oMer HCl
7~ - '.ryl -- B -- C -~ D - E
sti.mulate the motility of the museles o.~ the yastro-intestinal trae~. and, therefore, they ean k,e usecl ~or treating paralytie symptoms of these organs.
In the above formula A denotes hydrogen, alkyl, alkenyl, or alkenylcycloalkyl eaeh having up to 7 earbon atoms, an ~ -amino aci.d or a peptide with 2 or 3 amino aeids, preferably of the l~configuration, B denotes a d-amino acid or ;~-amino-isobutytric acid, C deno-tes glycine or azaglycine, D denotes phenylalanine which can be substituted in the benzene nueleus by methyl, methoxy, halogen, nitro or trifluoromethyl; dehydro- or hexahydrophenylalanine;
aza- or N-methylphenylalanine, and E denotes / R2 (a) -O-R1 or -N
in whieh R1, R2 and R3 are identieal or different and are hydrogen, alkyl with 1 -to 6 earbon atoms; eyelo-alkyl with 3 to 6 earbon atoms; alkenyleyeloalkyl with 4 to 8 earbon atoms; hydroxyalkyl or dihydroxyalkyl, thio alkyl or mereaptoalkyl with 1 to 6 earbon atoms;
aryl ~ith 6 to 10 carbon atoms; aralkyl with 7 to 11 earbon atoms, or R2 and R3 together denote polymethylene with 2 to 6 earbon atoms, or R1 denotes methyl-poly-e~hylene glyeol having a degree of polymerization of up to about 50, (b) an amino aleohol or an amino aeid, whieh on its part, may carry one of the groups deiined sub (a); or (e) homoserine or homocysteine thiolactone.
Important aceumulations of liquid and gas as a result o lae~ing spontaneous motillty of the ileum are a eharacteristic of post-operative intestinai atony.
They may hinder the s--.art of spontaneous motoricity by o~erstretchirly o:E t:he intestinal wall. ~s a further eonsequenee eLeetrolytes ancl liquids may exuclate i.nto ~L~7~40~L
- - 3 - HOE 79/F _ 7 the lumerl of the bowels resulting in cir:culatory brea~ dC?~ I d3n~jerous to life. This development is counteracted b~ the peptides of the invention.
The peptides of the invention stimulate the motoricity of the gastro-intestinal tract and the efferen-t urinary tract in dogs and men. They increase the restin~ tonus and the se~mental contraction activity of the intestines and, therefore, promote secondly the water resorption from the lumen of the bowels ti1eum).
They have also a motility increasing action on the muscles of the efferent urinary tract and, therefore, they are suitable to stop atonies of the gastro-intesti-nal tract and of the efferent urinary tract.
~his effect is surprising, the more so as the peptides according to the invention are, in principle, known from literature. They have been tested as to their morphium-like action as enkephaline analoys in the ileum of Guinea pigs of which they hinder the contrac-tion. It has not been realized, however, that this effect is reversed in some species; whereby these compounds become valuable medicaments.
Up to now, attempts have been made to remedy post-operative intestinal atonies, characterized by the lack of the spontaneous motility of the intestine, by ad-ministration of parasympathomimetics. But a treatment of this type involves the danger of undesired systemic cholinergic effect, which is not the case with the peptldes to be used according to the invention.
It is therefore, the object of the present invention to provide a method of usiny peptides of the formula I
for increasing the motility of the muscles of the gastro-intestinal tract and the urinary tract and treating paralytic symptoms of -these muscles.
Suitable amino acids for component A in the formula I are preferably amino acids occurr:ing in proteins and the simple metabolites thereof, such as ornithine, methionine sulfoxide or sulfone, homocysteine, or .; pyroglutamic acid.
o~ ~
- 4 - HOE 79/F_27~
Suitab:Le ~-d-amino acids for colriponent ~ in the formula I are preferably enantiomers of amino acid~
oecurring in nature, which may be substituted in the side chain. The amino yroup can be substitutea, for example, by alkanoyl, cycloalkanoyl, aroyl, or aralkanoyl ea~h having up to 10 carbon atoms, by alkyl-, cyclo-alkyl or aralkyl-oxycarbonyl each having up to 7 carbon atoms. Hydroxy groups or mercapto groups can oe etherified by alkyl, aryl or aralkyl each having up to 10 carbon atoms, and carboxy groups may carry the groupings defined sub E (a). Thioethers can be converted to sulfoxide or sulfone and aromatics can be substituted by halogen, methyl, methoxy, nitro, or 1:rifluoromethyl.
Another suitable ~-d-amino acid is norleucine.
The ~ -amino alcohols and ~i~-amino acids speci-fied sub E can be in the l~ or also d-configuration.
Their side chains can be subs-tituted as specified above for the amino acids mentioned sub B. Suitable amino alcohols are, in the first place, the reduction products -of the corresponding natural amino acids, for example prolinol or methioninol, which on its part may also be present as sulfoxide or sulfone.
Espccially good results are obtained with compounds in which component E is a methyl-polyethylene glycol having a degree of polymerization of up to 50. Compounds of this type are novel and are also a subject of the present invention.
They have the interesting property of increasing the effect of the basic peptide compound and to improve its solubility so that they make it possible to use the peptides, whieh are difficulty soluble for themselves, for the method of the invention.
Numerous representàtives of the peptides aecordiny to the invention are known from literature. In general, they are prepared by methods of peptide chemistr~ which are described in detail in a great number of publieations.
The peptides according to the invention are effective even :in a dose of 10 nanograms per kilogram althotlc3h no - adverse effeets are observed if they are adminl7texed in . ~ . ' , :
, .
~ 5 -- ~IOE 7g/F 278 higher doses. Uncler suitable conditions mor-phi.ne exhi-bits simi]ar effect, but only in an about 50 times highe-r~ dose. To obtain the same effect with carbaminoyl choline having a parasympathomimetric activity an about 10-fold dose in necessary. ~ence, the peptides according to the invention belong to the most active effectors of the motoricity of the gas'~ro-intestinal tract and the efferent urinary tract. It is known that they have a morphine-like effect bwt with the small doses required the hemato-encephalic barrier is not passed over after intravenous, subcutaneous or intra-nasal administration of the effective doses. Hence, in the amounts re~uired for the purposes of the invention they do not exhibit any effect in the central nervous system.
Variations of components A to D of the peptides do not change the quality of the described effect, they only result in a varying quantitative increase of the e~ffect as compared with the very weakly effective basic compound, i.e. natural enkephaline.
Depending on the compound used, doses of from 0.5 to 500 micrograms are given for men by intravenous administration or subcutaneous administration, whereas the dose for intranasal administration ranges from about 20 micrograms to 25 milligrams. In the case of resorption troubles, for example, the dose can be increased.
The compounds of the invention can be used for the treatment of post-operative atonies of the gastro-intestinal -tract and the efferent urinary tract They can also be used in the treatment of the Hirschsprung disease caused by an inherent megacolon. A therapy with the compounds of the invention has the advantage that the effect of the peptides can be counteracted at any time by administration of opiate antagonists.
The following e~amples illustrate the invention, they describe a characteristic syntllesis of a peptide according to the invention and the manufacture of pharrna-.
7 ~ 4 0 ~
~ 6 - HOE 79/F_278 eeutical preparatJons of pep-tides for their usc aecordirlg to -the iI~vention.
E X A M P l E
. . . _ r--D-L~s(For) G_~-Phe-Met~O-PEG3000-OMe a) Boc-Me -O-P~G3000 OM,e ~.0 g o commercia] polyethylerle glycol monomethyl ether having an average molecu]ar weight of 3,000 (PEG3 0OO-OMe) and 5.0 g of Boc~Met-O'H are dissolved in 50 ml of dimethyl formamide while gently heating. Ater 10 addition oE 2.0 g of 1-hydroxybenzotriazole and 4.5 g of dieyelohexyl earbodiimide, the mixture is left to stand for ~2 hours at room temperature. The reaction produet is then precipitated with ether and the preeipi-tation is repeated with ether from methylene chloride.
Yield 3.5 g.
b) II-Met O-PEG3000-oMer HCl
3.5 g of -the Boc-compound obtained as described sub (a) are dissolved in 10 ml of formic aeid and 1 ml oE
6N HCl is added. After 30 minutes the reaction product is precipitated with ether and reprecipitated with ether after dissolu-tion in methylene chloride. Yield 3.2g.
e) _os~yr~ u )-D-Lys(For)-Gly-Phe-Met-O-PEG3000-OMe 3.15 g of H-Met-O-PEG3 0OO-OMe, HCl and 2.0 g of Boe-Tyr(Bu )-D-Lys(For)-Gly-Phe-OH, prepared aceording 25 to DE-OS 2,933,947 in 15 ml of dimethyl formamide are mixed while stirring with 0.6 ml of N-ethylmorpholine, 0.5 g of 1--hydroxybenzotria~ole and 0.75 g of dicyclo-hexy] earbodiimide. Stirring is eontinued for 48 hours at room temperature whereupon the reaetion product is 30 preeipitated with ether, dissolved in methylene ehloride and preeipitated ayain ~ith e-ther. Yield 2.7 g.
d) _Tyr-D-I~y_(For)-Gly-Phe-Met-O-PEG3000 OMe hydroeh]oride 2.5 g oE the eompound obtained as deseribed sub (c) 35 is dissolved in 12 ml of for~,ie aeid and 1.2 ml of 6N HCl are added ~/hile stirring at OC. Ater 40 minutes the reactior-l product is precipi-tated with ether, dissolved in methyleIle ehloride and precipitated ayain with ether.
~7'74~
~ 7 - EIOE 7g/F 2-18 The crystalline precipiate is trituratecl with e-ther and dried :in V~CU3 o~er sulfuric acid. Yield 2.2 ~. The analysis of amlnv acids confirms the composition and peptide conten-t of the expected product.
1 mg of Tyr-d-Met G]y-Phe-methioninol sulfoxide or Tyr-d-Lys(For)--Gly-Phe-homocysteine thiolactone is dissolved in 1 li-ter of physiologic~l sodium chloride solution containing 1 % of phenyl ethanol. The solution is filtered under sterile conditions and 1 ml portions are filled into ampoules.
__ 250 mg of CH3-Tyr-d-Met-Gly-Phe-Met-NH2 or Tyr-d-Ser-Gly-Phe-Pro-OlI are dissolved in 1 liter of physiolo-gical sodium chloride solution containing 1 ~O of phenylethanol. The solution is filtered under sterile condi-tions and filled into spray bottles ejecting 0.2 ml of solution with each push.
,
6N HCl is added. After 30 minutes the reaction product is precipitated with ether and reprecipitated with ether after dissolu-tion in methylene chloride. Yield 3.2g.
e) _os~yr~ u )-D-Lys(For)-Gly-Phe-Met-O-PEG3000-OMe 3.15 g of H-Met-O-PEG3 0OO-OMe, HCl and 2.0 g of Boe-Tyr(Bu )-D-Lys(For)-Gly-Phe-OH, prepared aceording 25 to DE-OS 2,933,947 in 15 ml of dimethyl formamide are mixed while stirring with 0.6 ml of N-ethylmorpholine, 0.5 g of 1--hydroxybenzotria~ole and 0.75 g of dicyclo-hexy] earbodiimide. Stirring is eontinued for 48 hours at room temperature whereupon the reaetion product is 30 preeipitated with ether, dissolved in methylene ehloride and preeipitated ayain ~ith e-ther. Yield 2.7 g.
d) _Tyr-D-I~y_(For)-Gly-Phe-Met-O-PEG3000 OMe hydroeh]oride 2.5 g oE the eompound obtained as deseribed sub (c) 35 is dissolved in 12 ml of for~,ie aeid and 1.2 ml of 6N HCl are added ~/hile stirring at OC. Ater 40 minutes the reactior-l product is precipi-tated with ether, dissolved in methyleIle ehloride and precipitated ayain with ether.
~7'74~
~ 7 - EIOE 7g/F 2-18 The crystalline precipiate is trituratecl with e-ther and dried :in V~CU3 o~er sulfuric acid. Yield 2.2 ~. The analysis of amlnv acids confirms the composition and peptide conten-t of the expected product.
1 mg of Tyr-d-Met G]y-Phe-methioninol sulfoxide or Tyr-d-Lys(For)--Gly-Phe-homocysteine thiolactone is dissolved in 1 li-ter of physiologic~l sodium chloride solution containing 1 % of phenyl ethanol. The solution is filtered under sterile conditions and 1 ml portions are filled into ampoules.
__ 250 mg of CH3-Tyr-d-Met-Gly-Phe-Met-NH2 or Tyr-d-Ser-Gly-Phe-Pro-OlI are dissolved in 1 liter of physiolo-gical sodium chloride solution containing 1 ~O of phenylethanol. The solution is filtered under sterile condi-tions and filled into spray bottles ejecting 0.2 ml of solution with each push.
,
Claims (3)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A composition, suitable for stimulating the motility of the muscles of the gastro-intestinal tract and of the urinary tract, and for treatment of paralytic symptoms of the gastro-intestinal tract and the urinary tract, comprising at least one peptide of the formula I
A - Tyr - B - C - D - E
wherein A denotes hydrogen, alkyl, alkenyl, or alkenylcycloalkyl each having up to 7 carbon atoms, an .alpha.-amino acid or a peptide with 2 or 3 amiro acids, B denotes an .alpha.-amino acid or .alpha.-amino-isobutyric acid, C denotes glycine or azaglycine, D denotes phenylalanine which can be substituted in the benzene nucleus by methyl, methoxy, halogen, nitro or trifluoromethyl;
dehydro- or hexahydrophenylalanine; aza- or N-methylphenyl-alanine, and E denotes (a) -O-R1 or wherein, R1, R2 and R3 are identical or different and are hydrogen, alkyl with 1 to 6 carbon atoms; cycloalkyl with 3 to 6 carbon atoms; alkenylcycloalkyl with 4 to 8 carbon.atoms;
hydroxyalkyl or dihydroxyalkyl, thio alkyl or mercaptoalkyl with 1 to 6 carbon atoms; aryl with 6 to 10 carbon a.toms;
aralkyl with 7 to 11 carbon atoms, or R2 and R3 together denote polymethylene with 2 to 6 carbon atoms, (b) an amino alcohol or an amino acid, which on its part may carry one of the groups defined sub (a); or (c) homoserine or homocysteine thiolactone in association with a pharmaceutically acceptable carrier with the proviso that peptides of the formula H-Tyr-X-Gly-Phe-Met-Y, wherein X denotes D-Ala, D-Leu, D-Ile, D-Val, D-Phe, D-Tyr, D-Trp, D-Ser, D-Thr, D-Met, D-Glu, D-Gln, D-Asp, D-Asn, D-Lys or D-Arg and Y denotes NH2 or OH are excluded.
A - Tyr - B - C - D - E
wherein A denotes hydrogen, alkyl, alkenyl, or alkenylcycloalkyl each having up to 7 carbon atoms, an .alpha.-amino acid or a peptide with 2 or 3 amiro acids, B denotes an .alpha.-amino acid or .alpha.-amino-isobutyric acid, C denotes glycine or azaglycine, D denotes phenylalanine which can be substituted in the benzene nucleus by methyl, methoxy, halogen, nitro or trifluoromethyl;
dehydro- or hexahydrophenylalanine; aza- or N-methylphenyl-alanine, and E denotes (a) -O-R1 or wherein, R1, R2 and R3 are identical or different and are hydrogen, alkyl with 1 to 6 carbon atoms; cycloalkyl with 3 to 6 carbon atoms; alkenylcycloalkyl with 4 to 8 carbon.atoms;
hydroxyalkyl or dihydroxyalkyl, thio alkyl or mercaptoalkyl with 1 to 6 carbon atoms; aryl with 6 to 10 carbon a.toms;
aralkyl with 7 to 11 carbon atoms, or R2 and R3 together denote polymethylene with 2 to 6 carbon atoms, (b) an amino alcohol or an amino acid, which on its part may carry one of the groups defined sub (a); or (c) homoserine or homocysteine thiolactone in association with a pharmaceutically acceptable carrier with the proviso that peptides of the formula H-Tyr-X-Gly-Phe-Met-Y, wherein X denotes D-Ala, D-Leu, D-Ile, D-Val, D-Phe, D-Tyr, D-Trp, D-Ser, D-Thr, D-Met, D-Glu, D-Gln, D-Asp, D-Asn, D-Lys or D-Arg and Y denotes NH2 or OH are excluded.
2. A composition as claimed in claim 1 in which when component A is an .alpha.-aminoacid or a peptide with 2 or
3 amino acids it has the 1-configuration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000443575A CA1184901A (en) | 1979-10-16 | 1983-12-16 | Method of using motility increasing peptides |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19792941790 DE2941790A1 (en) | 1979-10-16 | 1979-10-16 | USE OF MOTIVITY-INCREASING PEPTIDES |
| DEP2941790.1 | 1979-10-16 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000443575A Division CA1184901A (en) | 1979-10-16 | 1983-12-16 | Method of using motility increasing peptides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1177401A true CA1177401A (en) | 1984-11-06 |
Family
ID=6083575
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000362430A Expired CA1177401A (en) | 1979-10-16 | 1980-10-15 | Method of using motility increasing peptides |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0028716B1 (en) |
| JP (1) | JPS5668617A (en) |
| AT (1) | ATE23441T1 (en) |
| AU (1) | AU541547B2 (en) |
| CA (1) | CA1177401A (en) |
| DE (2) | DE2941790A1 (en) |
| ZA (1) | ZA806328B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5756447A (en) * | 1980-07-17 | 1982-04-05 | Sandoz Ag | Novel pentapeptides |
| DE3163199D1 (en) * | 1980-07-17 | 1984-05-24 | Sandoz Ag | Novel pentapeptides, processes for their production, pharmaceutical compositions comprising said pentapeptides and their use |
| DE3267380D1 (en) * | 1981-06-22 | 1985-12-19 | Ici Plc | Peptides and pseudopeptides in which the n terminus bears two substituents |
| SU1348343A1 (en) * | 1984-07-16 | 1987-10-30 | Всесоюзный кардиологический научный центр АМН СССР | Hexapeptide possessing antipancreatonecrotic activity |
| SU1470739A1 (en) * | 1984-07-16 | 1989-04-07 | Всесоюзный кардиологический научный центр АМН СССР | Hexapeptide displaying hepatoprotective traits |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2730851A1 (en) * | 1976-07-19 | 1978-01-26 | Sandoz Ag | NEW POLYPEPTIDE DERIVATIVES, THEIR PRODUCTION AND USE |
| NO773013L (en) * | 1976-09-01 | 1978-03-02 | David Howard Coy | PROCEDURES FOR THE PREPARATION OF METHIONIN-ENKEFALIN DERIVATIVES |
-
1979
- 1979-10-16 DE DE19792941790 patent/DE2941790A1/en not_active Withdrawn
-
1980
- 1980-10-11 EP EP80106211A patent/EP0028716B1/en not_active Expired
- 1980-10-11 DE DE8080106211T patent/DE3071825D1/en not_active Expired
- 1980-10-11 AT AT80106211T patent/ATE23441T1/en not_active IP Right Cessation
- 1980-10-15 CA CA000362430A patent/CA1177401A/en not_active Expired
- 1980-10-15 AU AU63284/80A patent/AU541547B2/en not_active Ceased
- 1980-10-15 ZA ZA00806328A patent/ZA806328B/en unknown
- 1980-10-16 JP JP14373680A patent/JPS5668617A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| ZA806328B (en) | 1981-10-28 |
| EP0028716B1 (en) | 1986-11-12 |
| EP0028716A2 (en) | 1981-05-20 |
| AU6328480A (en) | 1981-04-30 |
| DE2941790A1 (en) | 1981-04-30 |
| DE3071825D1 (en) | 1987-01-02 |
| JPS5668617A (en) | 1981-06-09 |
| AU541547B2 (en) | 1985-01-10 |
| ATE23441T1 (en) | 1986-11-15 |
| EP0028716A3 (en) | 1981-12-23 |
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Legal Events
| Date | Code | Title | Description |
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| MKEX | Expiry |