GB1562067A - Pentapeptides - Google Patents
Pentapeptides Download PDFInfo
- Publication number
- GB1562067A GB1562067A GB5228/78A GB522878A GB1562067A GB 1562067 A GB1562067 A GB 1562067A GB 5228/78 A GB5228/78 A GB 5228/78A GB 522878 A GB522878 A GB 522878A GB 1562067 A GB1562067 A GB 1562067A
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- GB
- United Kingdom
- Prior art keywords
- resin
- compound
- phenylalanyl
- formula
- tyrosyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
- C07K14/70—Enkephalins
- C07K14/702—Enkephalins with at least 1 amino acid in D-form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Description
(54) PENTAPEPTIDES
(71) We, AMERICAN HOME PRODUCTS CORPORATION, a corporation organised and existing under the laws of the State of Delaware, United States of America, of 685,
Third Avenue, New York 10017, New York, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement:
This invention relates to peptides, to processes for their preparation and to pharmaceutical compositions containing them.
Enkephalin, a natural oPiate receptor agonist in brain, has been identified (see Hughes et al.,Nature,258,577(1975l as a mixture of two pentapeptides: H-Tyr-Gly-Gly-Phe-Met-OH (methionine-enkephalin) and H-Tyr-Gly-Gly-Phe-Leu-OH (leucine-enkephalin). Both peptides mimic the ability of morphine to block electrically evoked contractions of mouse vas deferens and guinea pig ileum, and both inhibit the stereospecific receptor binding of the opiate antagonist 3H-naloxone in brain homogenates. It has been reported that methionineenkephalin and leucine-enkephalin, when administered by injection in the brain ventricle in rats, induce a profound analgesia that is fully reversible by naloxone. (See Beluzzi et al.,
Nature, 260, 625 (1976)). The enkephalins are inactive peripherally, however, and it is beleived that the enkephalins are rapidly destroyed by blood enzymes and/or are poorly transported across the blood-brain barrier.
Various structural variations of methionine-enkephalin and leucine-enkephalin are described in the literature. For example, the pentapeptide H-Tyr-Gly-Gly-Phe-Thr-OH, wherein the fifth amino acid residue methionine or leucine) is replaced by threonine, is described by Chang et al., Life Sciences, 18, 1473 (1976). Similarly, a long acting synthetic pentapeptide, H-Tyr-D-Ala-Gly-Phe-Met-NH2 is described in Pert et al., Science, 194, 330 (1976;like the natural enkephalins, it is inactive peripherally, for example upon intravenous administration.
The present invention concerns synthetic pentapeptides which are able to produce an analgesic effect in warm blooded animals upon peripheral administration as evidenced by standard test procedures.
The invention provides pentapeptides of the formula: H-Tyr-D-Ala-Gly-Phe-X (1) wherein X is D-Leu-OH, D-Leu-NH2, D-Met-OH, or D-Met-NH2; or a pharmaceutically acceptable salt thereof.
This invention also includes processes for preparing the pentapeptides by known methods, e.g. building up the molecule by condensing the requisite amino acids /amide precursors, protected and/or activated if necessary, to give the desired sequence, deprotecting and if desired isolating as a pharmaceutically acceptable salt. Such methods are described in the literature, for example, Schroder and Lubke - The Peptides-1, Academic Press 1965. In such processes the final step is usually removal of terminal protecting groups.
The compounds of the invention may also be prepared by typical solid phase procedures on resins. Thus this invention also provides a process for preparing a compound of formula I which comprises reacting the requisite suitably protected and/or activated amino acids under solid phase synthesis conditions on a resin support, and deprotecting and cleaving the peptide from the resin; if desired isolating as a pharmaceutically acceptable salt.
A benzhydrylamine resin gives a peptide with an amide terminal group. A chloromethyl resin gives a peptide with a carboxy terminal group. The peptide can be cleaved from the resin by HF, and pufified by partition chromatography on Sephadex G-25 using the system n-butano.-acetic acid-water (BAW), 4:1:5 by volume. (SEPHADEX is a Registered Trade
Mark).
Accordingly this invention also provides intermediates for compounds of formula I, which intermediates have the formula (II)
wherein R and Rl are protecting groups for the amino group and the hydroxyl group respectively of tyrosine and Xl is D-Leu-R2 or D-Met-R2 wherein R2 represents -0 (carboxy protecting group), -NH2, or a solid phase resin support in which the link between the peptide and a phenyl of the resin support is represented by one of the formulae:
In the case of the pharmacologically acceptable salts of the invention, there is included
addition salts of the pentapeptides with non-toxic, pharmaceutically acceptable acids. Suit
able acids both organic and inorganic, will be readily apparent to those skilled in the art, for example: hydrochloric, phosphoric, maleic, acetic, citric, succinic and malic. The salts are prepared and isolated by conventional methods from the corresponding pentapeptides.
The symbols used for representing the amino acid residues in formula I and in the other formulae employed herein are defined according to the IUPAC-IUB Commission on
Biochemical Nomenclature Recommendations (1971), Archives of Biochemistry and
Biophysics, 150, 1 - 8 (1972). All chiral amino acid residues identified without prefix in this specification and in the claims are in the natural or kconfiguration. Amino acid residues preceded with the prefix "D-" are in the D, or "unnatural" configuration.
The analgesic activity of the compounds of the invention can be demonstrated in rats using the rat-tail flick method of D'Amour and Smith, J. Pharmacol. Exp. Therap., 72, 74 (1941).
In this procedure, a single intravenous dose of from 0.5 to 20 mg/kg, will produce analgesia in the rat. Preferably, a dose of from 1 to 10 mg/kg is employed. The exact dose to be employed will vary depending on the particular compound employed and the degree of analgesia desired. The determination of the precise dose to produce the desired effect will be readily ascertained by those skilled in the art. With the compound H
Tyr-D-Ala-Gly-Phe-D-Leu-NH2, the following results were obtained:
Dose No. showing analgesialNo. Tested
10 mg.lkg. i.v. 6/6
2.5 mg.lkg. i.v. 6/6
0.625 mg./kg. i.v. 4/6
0.3125 mg.lkg. i.v. 1/6
This invention also provides pharmaceutical compositions comprising the pentapeptides of the invention and pharmaceutically acceptable carriers.
The following examples more specifically set forth a method of synthesis of the compounds of the invention.
EXAMPLE l Synthesis of H- Tyr-D-Ala-Gly-Phe-D-Leu-NH2 10 gms. benzhydrylamine HC1 resin (Beckman) was neutralized in a solid phase reactor by washing 2 times with 20% by volume triethylamine in dimenthylformamide followed by washing 3 times with dimethylformamide. (BECKMAN is a Registered Trade Mark).
The above resin was then reacted in a solid phase reactor with 9.2 gms. t-Boc-D-Leucine and 6.0 mls. diisoproplycarbodiimide overnight in dimethylformamide (DMF) at room temperature (TR). The following morning the resin was washed in the reactor 2x with dimethylformamide, 2x with methylene chloride (MeC12), 2x with methanol, and 3x with methylene chloride.
The ninhydrin test for free amino groups on the resin was negative at this point so the next addition was effected. The resin was deprotected in the reactor with 30% by volume trifluoroacetic acid in methylene chloride containing 0.5% w/v dithioerythritol. This was followed by washing 2x with methylene chloride, once with DMF 2x with 20% by volume triethylamine in DMF and 3x with DMF.
The washed resin was then reacted with 10.6 gms. t-Boc-L-phenylalanine and 6.0 mls.
diisopropylycarbodiimide overnight at TR in the same reactor. After washing 2x with DMF, 2x with MeC12, 2x with MeOH, and 3x with MeC12; the resin was ninhydrin negative and the previous deprotection step was repeated. The resin was then reacted as previously described with 7.0 gms. t-Boc-glycine and 6.0 mls. diisopropylcarbodiimide (DIC). After reaction overnight and washing as previously, the resin was still ninhydrin positive so was further reacted with 4 gms. t-Boc-glycine and 3 mls. DIC as described.
The following day after washing in the usual manner the resin was ninhydrin negative and was deprotected as previously described and coupled with 7.5 gms. t-Boc-D-alanine and 6.0 mls. DIC as previously described for the other couplings. After reacting overnight the resin was still ninhydrin positive so was recoupled with 4.0 gms. of t-Boc-D-alanine and 3.0 mls.
DIC overnight. After washing as previously described for this step, the resin was ninhydrin negative so was deprotected as previously described for this step and coupled with 18 gms.
t-Boc-O-2,6-dichlorobenzyl-L-tyrosine and 6.0 mls. DIC as previously described. After reacting overnight and washing, the resin was still slightly ninhydrin (+) so was further reacted with 9 gms. Boc-0-2,6-dichlorobenzyl-L-tyrosine and 3.0 mls. DIC overnight. The resin after washing was ninhydrin negative so was finally washed with methylene chloride 2x and twice with diethyl ether and dried over KOH in vacuo to give t-butyloxycarbonyl-0-2, 6-dichlorobenzyl-L-tyrosyl- D-alanylglycyl-L- phenylalanyl-D-leucyl- benzhydrylamine resin.
Cleavage of the pep tide from the resin:
10 gms. of the above dried resin were cleaved with hydrogen fluoride in the presence of 8 mls. of anisole for 1 hr. at 0 C. and the acid removed in vacuo overnight. The following morning, the resin was triturated with diethyl ether to remove anisole, dried with a gentle stream of nitrogen, and triturated twice with 40 mls. of 0.2N HOAc. Lyophylization of the acetic acid gave 1.3 gms. of product with Rf 0.52 on TLC (silica gel BAW 4:1:5 by volume) and was essentially homogeneous as judged by ninhydrin or chlorine peptide spray. Chlorine peptide spray containing inter alia) 1% soluble starch and 1% KI is described in "Solid Phase
Peptide Synthesis" by Stewart and Young, Freeman & Co., San Fransisco, 1969, at pages 62 and 63.
Purification
Partition chromatography of 450 mgs. of the cleaved peptide on Sephadex G-25F gave a homogeneous product (224 mgs) with an Rf of 0.52 on TLC silica gel BAW 4:1:5 by volume.
Amino acid analysis of product: Gly 1.0, D-Ala 0.99, D-Leu 1.04, Tyr 1.0, Phe 0.97, NH3
1.0.
EXAMPLE 2
Synthesis of H- Tyr-D-Ala- Gly-Phe-D-Met-NH2 10 gms. benzyhydrylamine resin and 10 gms. Boc-D-methionine were coupled in the manner of the previous example, the four additional amino acids then coupled as in the previous example except that 5.4 gms. of 1-hydroxybenzotriazole were added in addition at each coupling, with eliminated the need to recouple at each step.
Cleavage from the resin, t-butyloxycarbonyl-0-2,6-dichlosobenzyl-L- tyrosyl-Dalanylglycyl- L-phenylalanyl-D- methionyl-benzhydrylamine resin, and purification by partition chromatography as in Example 1 gave the desired peptide in homogeneous form.
EXAMPLE 3
Synthesis of H- Tyr-D-Ala- Gly-Phe-D-Leu- OH 10 gms. t-Boc-D-leucine in 6.0 mls. EtOH and 20 mls. of water were neutralized with
CsHCO3 evaporated to dryness and dried over KOH in vacuo. 5 gms. of this product and 15 gms. of chloromethyl resin (Merrifield resin) were stirred in DMF 48 hrs. at Tr. After washing the resin with DMF, 90%v/v DMF, in water methylene chloride and EtOH, it was dried. The substitution was approximately 0.3 meq. H-D-Leu-OH/gm. as determined by amino acid analysis.
The succeeding amino acids were coupled to 10 gms. of the above resin in the manner described for the previous examples, using 1-hydroxybenzotriazole at each coupling to give t-butyloxycarbonyl-0-2, 6- dichlorobenzyl-L-tyrosyl -D-alanylglycyl -L-Phenylalanyl-D
-leucyl-oxymethyl resin.
Example 4
Synthesis of H-Tyr-D-Ala-Gly-Phe-D-Met-OH
The title compound is prepared in the manner of Example 3, substituting D-Met for D-Leu and cleaving from the peptides resin: t-butyloxycarbonyl- 0-2,6-dichlorobenzyl-L- tyrosyl
D-alanylgIycyl- L-phenylalanyl-D-methionyl- oxymethyl resin.
WHAT WE CLAIM IS:
1. A pentapeptide compound of the formula H-Tyr-D-Ala-Gly-Phe-X (1) wherein X is D-Leu-OH, D-Leu-NH2, D-Met-OH, or D-Met-NH2; or a pharmaceutically acceptable salt thereof.
2. L-Tyrosyl-D-alanylglycyl-L-phenylalanyl-D-leucine.
3. L-Turosyl-D-alanylglycyl-L-phenylalanyl-D-leucinamide.
4. L-Tyrosyl-D-alanylglycyl-L-phenylalanyl-D-methionine.
5. L-Tyrosyl-D-alanylglycyl-L-phenylalanyl-D-methioninemide, 6. A compound as claimed in any one of Claims 1 to 5 when in the form of a hydrochloric, phosphoric, maleic, acetic, citric, succinic or malic acid salt.
7. A compound of formula (II)
wherein R and R' are protecting groups for the a-amino group and the hydroxyl group respectively of tyrosine and Xl is D-Leu-R2 or D-Met-R2 wherein R2 represents -0(carboxy protecting group), -NH2, or a solid phase resin support in which the link between the peptide and a phenyl of the resin support is represented by one of the formulae:
8. T-Butyloxycarbonyl-0-2,6-dichlorobenzyl-L-tyrosyl- D-alanylglycyl-L-phenylalanyl
D-leucyl-benzhydrylamine resin.
9. t-Butyloxycarbonyl-0-2,6-dichlorobenzyl-L-tyrosyl- D-alanylglycyl-L-phenylalanyl
D-methionyl-benzhydrylamine resin.
10. t-Butyloxycarbonyl-0-2,6-dichlorobenzyl-L-tyrosyl- D-alanylglycyl-L-phenylalanyl
D-leucyl-oxymethyl resin.
11. t-Butyloxycarbonyl-0-2,6-dichlorobenzyl-L-tyrosyl- D-alanylglycyl-L-phenylalanyl
D-methionyl-oxymethyl resin.
12. A process for preparing a compound of formula I as defined in Claim 1 wherein Xis D-Leu-NH2 or D-Met-NH2 which comprises coupling the requisite amino acids and amino acid amide, protected and/or activated if necessary, to give the desired sequence, deprotect- ing, and if desired isolating as a pharmaceutically acceptable salt.
13. A process for preparing a compound of formula I as defined in Claim 1 wherein X is
D-Leu-OH or D-Met-OH which comprises coupling the requisite amino acids, protected and/or activated if necessary, to give the desired sequence, deprotecting, and if desired isolating as a pharmaceutically acceptable salt.
14. A process for preparing a compound of formula I as defined in Claim 1 which comprises deprotecting a compound as claimed in Claim 7, if desired isolating as a pharmaceutically acceptable salt.
15. A process for preparing a compound of formula I as defined in Claim 1, which comprises condensing the requisites amino acids protected and/or activated if necessary, under solid phase synthesis conditions on a resin support, deprotecting and cleaving the compound from the resin; if desired isolating as a pharmaceutically acceptable salt.
16. A process as claimed in Claim 10 wherein the resin is a benzhydrylamine resin and the peptide prepared has an amide terminal group.
17. A process as claimed in Claim 15 in which the resin is a chloromethyl resin and the peptide prepared has a carboxy terminal group.
18. A process as claimed in Claim 15 for preparing a compound of formula I, as defined in claim 1. substantially as hereinbefore described with reference to any one of Examples 1 to 4.
19. A compound of formula I, as defined in claim 1, whenever prepared by a process as
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (20)
1. A pentapeptide compound of the formula H-Tyr-D-Ala-Gly-Phe-X (1) wherein X is D-Leu-OH, D-Leu-NH2, D-Met-OH, or D-Met-NH2; or a pharmaceutically acceptable salt thereof.
2. L-Tyrosyl-D-alanylglycyl-L-phenylalanyl-D-leucine.
3. L-Turosyl-D-alanylglycyl-L-phenylalanyl-D-leucinamide.
4. L-Tyrosyl-D-alanylglycyl-L-phenylalanyl-D-methionine.
5. L-Tyrosyl-D-alanylglycyl-L-phenylalanyl-D-methioninemide,
6. A compound as claimed in any one of Claims 1 to 5 when in the form of a hydrochloric, phosphoric, maleic, acetic, citric, succinic or malic acid salt.
7. A compound of formula (II)
wherein R and R' are protecting groups for the a-amino group and the hydroxyl group respectively of tyrosine and Xl is D-Leu-R2 or D-Met-R2 wherein R2 represents -0(carboxy protecting group), -NH2, or a solid phase resin support in which the link between the peptide and a phenyl of the resin support is represented by one of the formulae:
8. T-Butyloxycarbonyl-0-2,6-dichlorobenzyl-L-tyrosyl- D-alanylglycyl-L-phenylalanyl
D-leucyl-benzhydrylamine resin.
9. t-Butyloxycarbonyl-0-2,6-dichlorobenzyl-L-tyrosyl- D-alanylglycyl-L-phenylalanyl
D-methionyl-benzhydrylamine resin.
10. t-Butyloxycarbonyl-0-2,6-dichlorobenzyl-L-tyrosyl- D-alanylglycyl-L-phenylalanyl
D-leucyl-oxymethyl resin.
11. t-Butyloxycarbonyl-0-2,6-dichlorobenzyl-L-tyrosyl- D-alanylglycyl-L-phenylalanyl
D-methionyl-oxymethyl resin.
12. A process for preparing a compound of formula I as defined in Claim 1 wherein Xis D-Leu-NH2 or D-Met-NH2 which comprises coupling the requisite amino acids and amino acid amide, protected and/or activated if necessary, to give the desired sequence, deprotect- ing, and if desired isolating as a pharmaceutically acceptable salt.
13. A process for preparing a compound of formula I as defined in Claim 1 wherein X is
D-Leu-OH or D-Met-OH which comprises coupling the requisite amino acids, protected and/or activated if necessary, to give the desired sequence, deprotecting, and if desired isolating as a pharmaceutically acceptable salt.
14. A process for preparing a compound of formula I as defined in Claim 1 which comprises deprotecting a compound as claimed in Claim 7, if desired isolating as a pharmaceutically acceptable salt.
15. A process for preparing a compound of formula I as defined in Claim 1, which comprises condensing the requisites amino acids protected and/or activated if necessary, under solid phase synthesis conditions on a resin support, deprotecting and cleaving the compound from the resin; if desired isolating as a pharmaceutically acceptable salt.
16. A process as claimed in Claim 10 wherein the resin is a benzhydrylamine resin and the peptide prepared has an amide terminal group.
17. A process as claimed in Claim 15 in which the resin is a chloromethyl resin and the peptide prepared has a carboxy terminal group.
18. A process as claimed in Claim 15 for preparing a compound of formula I, as defined in claim 1. substantially as hereinbefore described with reference to any one of Examples 1 to 4.
19. A compound of formula I, as defined in claim 1, whenever prepared by a process as
claimed in any one of Claims 12 to 18.
20. A pharmaceutical composition comprising a compound of formula I as defined in
Claim 1 and a pharmaceutically acceptable carrier.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US76787277A | 1977-02-11 | 1977-02-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1562067A true GB1562067A (en) | 1980-03-05 |
Family
ID=25080827
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB5228/78A Expired GB1562067A (en) | 1977-02-11 | 1978-02-09 | Pentapeptides |
Country Status (2)
Country | Link |
---|---|
JP (1) | JPS53108941A (en) |
GB (1) | GB1562067A (en) |
-
1978
- 1978-02-09 GB GB5228/78A patent/GB1562067A/en not_active Expired
- 1978-02-10 JP JP1482078A patent/JPS53108941A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
JPS53108941A (en) | 1978-09-22 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PS | Patent sealed | ||
PCNP | Patent ceased through non-payment of renewal fee |