GB1577115A - Container closure units - Google Patents
Container closure units Download PDFInfo
- Publication number
- GB1577115A GB1577115A GB31194/76A GB3119476A GB1577115A GB 1577115 A GB1577115 A GB 1577115A GB 31194/76 A GB31194/76 A GB 31194/76A GB 3119476 A GB3119476 A GB 3119476A GB 1577115 A GB1577115 A GB 1577115A
- Authority
- GB
- United Kingdom
- Prior art keywords
- alkyl
- hydrogen
- methyl
- phenyl
- group
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- General Health & Medical Sciences (AREA)
- Biophysics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
(54) OLIGOPEPTIDES
(71) We, RECKITT & COLMAN PRODUCTS LIMITED, a British Company, of
P.O. Box 26, 1/17 Burlington Lane London W4, 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 therapeutic compositions thereof.
According to this invention there are provided compounds of the formula:
wherein
R1 is hydrogen, alkyl C1-4, alkenyl C3-5, propargyl, cycloalkyl C3-7 methyl or phenyl-alkyl
C1-3;
R is hydrogen or alkyl C1-4;
R8 is alkyl Cl ", cycloalkyl C36, -CH(CH2OH) alkyl C1-5, cycloalkyl C3-6 alkyl C1.5, phenyl, phenyl-alkyl C 5, -5, CpH2pXCqH2q+1 (where p is 2-6, q is 1-5 and X is oxygen or sulphur), -CH(CH2OH)(CH2)2SMe or hydrogen;
R9 is hydrogen, alkyl C1.111, phenyl or phenyl-alkyl C1-6;
or NR8R9 may be pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, which groups may be substituteld by alkyl C1-3 or phenyl;
B is a D-serine or D-threonine radical or an alkyl C1-4 ether thereof, or a D-proline,
D-tryptophan. D-phenylalanine or D-methionine radical or the group -NH-CR'R7-Co (where R6 is alkyl C1- 5 and R7 is hydrogen or methyl) the group having the D-configuration or the group
(where n is 2-5); the group Phe may optionally be N-substituted by methyl; and the acid addition salts thereof.
In an aspect of the invention there are provided compounds of Formula I
wherein
R1 is hydrogen, alkyl C1-4, alkenyl C3-5, propargyl, or cycloalkyl C3-7 methyl C;
R2 is hydrogen or alkyl C1-4; Rx is alkyl C3 6 or (CH2)3SCH3; R9 is hydrogen;
B is a D-serine. D-threonine, D-proline, D-phenylalanine or D-methionine radical or the group -NH-CR6R7-CO (where R6 is alkyl C1-5 and R7 is hydrogen or methyl) the group having the D-configuration or the group
(where n is 2-5); acid addition salts thereof.
In a preferred aspect of the invention there are provided compounds of Formula I represented by the formula
wherein
R1 is hydrogen, alkyl C1-4, alkenyl C3-5, propargyl, cycloalkyl C3-7 methyl or phenyl-alkyl
C1-3;
R2 is hydrogen or alkyl C1-4;
B is a D-serine or D-threonine radical or an alkyl C1-4 ether thereof, or a D-proline,
D-phenylalanine or D-methionine radical or the group -NH-CR6R7-CO (where R6 is alkyl
C1-5 and R7 is hydrogen or methyl) the group having the D-configuration or the group
(where n is 2-5);
R8 is alkyl C1-10, cycloalkyl C3-6, -CH(CH2OH) alkyl C1-5, cycloalkyl C3-6 alkyl C1-5,
phenyl, phenyl-alkyl C1-5, -CpH2pXCqH2q+1 (where p is 2-6, q is 1-5, and X is oxygen or
sulphur) or -CH(CH2OH)(CH2)2SMe;
R9 is hydrogen, alkyl C1-10, phenyl or phenyl-alkyl C1-6;
or NR8R9 may be pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, which groups may be substituted by alkyl C1-3; and the acid addition salts thereof.
In a most preferred aspect of the invention there are provided compounds of the formula:
wherein
R1 is hydrogen, methyl, cyclopropylmethyl, cyclobutylmethyl, allyl, dimethylallyl or phenethyl:
R2 is hydrogen or methyl;
B is a D-alanine, D-leucine, D-valine or D-α-minobutyric acid, α-aminoisobutyric acid radical or the group
(where N is 2-5):
R8 is alkyl C1-8, phenyl, phenyl-alkyl C1-5 or -CpH2pXCqH2q+1 (where p is 3-6, q is 1-4 and X is oxygen or sulphur);
R9 is hydrogen, alkyl C1-5, phenyl or phenyl-alkyl C1-5; and the acid addition salts thereof.
In a further aspect of the invention there are provided compounds of the formula:
wherein R1 is hydrogen, alkyl C1-4, allyl, propargyl, or benzyl;
R2 is hydrogen or alkyl C1-4;
B is a D-alanine, D-a-alkyl C, 5 alanine, D-valine, D-norvaline, D-leucine, D-isoleucine,
D-norleucine, D-proline or D-tryptophan radical;
R8 is hydrogen or alkyl C1.10; R9 is hydrogen or alkyl C"(); or NR8R9 may be pyrrolidino, piperidino or morpholino; the group Phe may optionally be N-substituted by alkyl C1.10; and the acid addition salts thereof.
The symbols used herein for amino-acid derivatives are those customarily used in peptide chemistry such as are set out in Biochem. J. 126, 773 (1972). All amino-acid residues are of the natural or L-configuration unless specified otherwise.
The invention also provides therapeutic compositions comprising a compound of the formula, or a pharmaceutically-acceptable acid addition salt thereof, in association with a pharmaceutically acceptable diluent or carrier.
The compounds of the invention exhibit pharmacological activity when tested in the transmurally stimulated mouse vas deferens preparation described in Henderson G,
Hughes J, Kosterlitz H, Brit. J. Pharmacol. 46, 764-766, (1972). Types of drug which show activity in this test include local anaesthetics, smooth muscle depressants, adrenegeric neuron blocking agents, presynaptic a-receptor stimulants, ss-stimulants and narcotic agonists. The compounds of the invention may therefore have use in man where such types of drug are employed. Additionally since the compounds are peptides they may be used as intermediates in the preparation of further peptides which include such amino-acid sequences.
The compounds of the invention may be prepared by the standard methods of peptide chemistry.
Thus they may be produced by sequential coupling, usually from C-terminus, of suitably protected and activated amino acids by either classical solution methods or solid phase procedures, or by coupling fragments consisting of suitably protected peptides,
Details concerning the selection of protecting groups and methods for their incorporation as well as suitable reaction conditions for forming amido (peptide) linkages and removal of protecting groups may be found in the following references:
(a) Houben Weyl
Methoden der Organischen Chemie Vol. 16
Parts I and II Synthese von Peptiden (Thiem 1974)
(b) Schrdder & Lübke "The Peptides"
Academic Press (1965)
Thus the compounds of formula I may be prepared by condensing a compound of formula II Y-M,-OH II where Y is a N-protecting group and M1 is a protected amino acid or peptide residue, with a compound of formula III H-M2-Q III
where M2 is a protected amino acid or peptide residue and Q is a carboxyl protecting group. The coupling of II and III may be achieved by the standard methods of peptide synthesis either with or without isolation of the activated component corresponding to the compound of formula II. The removal of either of the protecting groups Y or Q from the coupled product affords a further compound analogous to respectively formula III or formula II which can be further coupled with respectively a compound of formula II or III.
This process is then repeated until the desired peptide is constructed.
The invention is illustrated by the following non-limiting Examples in which temperatures are in degrees centigrade.
The following abbreviatives are used throughout
BOC t-Butyloxycarbonyl Bu' t-Butyl
Z Benzyloxycarbonyl
ONSu N-Hydroxysuccinimido
DCCI Dicyclohexylcarbodiimide
DCU Dicylohexylurca HONSu N-Hydroxysuccinimide
NMM N-Methylmorpholine
DMF Dimethylformamide
DCHA Dicyclohexylamine
DME 1,2-Dimethoxyethane
i-Am Isoamyl
Tos Tosylate
TMG Tetramethylguanidine
The various compounds and intermediates were examined by thin layer chromatography (t.l.c.) on Kieselgel GF254 plates using the following systems where ratios are volume/ volume:- 7B ethyl acetate, pyridine, acetic acid, water 60:20:6:11 7C ethyl acetate, pyridine, acetic acid, water 120:20:6:11 7D ethyl acetate, pyridine, acetic acid, water 240:20:6:11 8A Chloroform, isopropanol 3:1 3A Chloroform, methanol, acetic acid. water 60:1:2:3 EXAMPLE 1
L-Tyrosyl-D-alanylglycyl-L-phenylalanine-3-methylbutylamide
This was prepared according to the following method:
eTyr A1a Gly Phe Z --- ONSu H -- OH ~ ~ 'Z ----- - OH (il) But BOO ONSu H OH Z N H i-Am t 0 (III) /E BOC - , -OH Tos H2 - --------------- - NH i-Am (I) 1 (IV, But BO C / ~ . NH . NH -NH i-Am (V) H - NH i-Am (VI) (a) N-t-Butyloxycarbonyl-O-t-butyl-L-tyrosyl-D-alanine (I)
BOC-Tyr(But)-OH (2.5 g) was dissolved in DME, cooled in an ice-salt bath and then
HONSu (0.853 g) and DCCI (1.53 g) were added. The reaction mixture was allowed to attain room temperature and stirred overnight. DCU was filtered off and the solvent evaporated. The residue was dissolved in DMF (5 ml) and added at room temperature to a solution of D-alanine (0.66 g) in DMF (5 ml) and water (1 ml) in the presence of TMG (0.86 g). The reaction mixture was stirred overnight, the solvent was evaporated. and the residue treated with water (100 ml). The aqueous solution was extracted with ethyl acetate (2 x 50 ml) and acidified to pH 4 with 1OC/o wt/vol aqueous citric acid. The mixture was extracted with ethyl acetate (2 x 100 ml) and the combined organic extracts washed with water until free of acid. and dried (Na.SO4). On evaporation of this solvent a gum was obtained which crystallised from ethyl acetate to give the the dipeptide derivative (I) (1.3 g, 43% m.p. 186-187 Rf7C = 0.65; Rf8A = 0.25.
(b) Benzyloxycarbonylglycyl-L-phenylalanine (II)
Z-Gly-ONSu (20 g) was added to a solution of L-phenylalanine (12.36 g) in DMF (50 ml) and water (5 ml) in the presence of TMG (8.69 g) and the solution stirred at room temperature for 18 hrs. The reaction was worked up in a similar manner as described in (a) above. The product was crystallised from ethyl acetate/petroleum ether to yield the dipeptide derivative (II) (22 g, t)5%) m.p. 123.5-124 Rf7D = 0.3.
(c) Benzyloxycarbonylglycyl-L-phenylalanine-3-methylbutylamide (III)
Z-Gly-Phe-OH (2 g) and isoamylamine (0.588 g) were dissolved in DMF (15 ml) and cooled in an ice-salt bath when HONSu (1.42 g) and DCCJ(l.28 g) were added and the reaction mixture allowed to warm up to room temperature. After stirring for 18 hrs the
DCU was filtered off and the solvent evaporated. The residue was dissolved in ethyl acetate (150 ml), washed with a saturated solution of sodium bicarbonate (3 x 50 ml), 10% wt/vol aqueous citric acid solution (3 x 50 ml) and finally with water until free from acid and then with a saturated brine solution. The organic phase was dried (Na2SO4) and evaporated to yield a solid which crystallised from ethyl acetate/petroleum ether to yield (III) (1.7 g, 70%) m.p. 128-129 .
(d) N-t-Butyloxycarbonyl-O-t-butyl-L-tyrosyl-D-alanylglycyl-L-phenylalanine-3methylbutylamide (V)
(i) Z-Gly-Phe-NH-i-Am (1.5 g) was hydrogenolysed at room temperature in DMF (15 ml) overnight in the presence of p-toluenesulphonic acid monohydrate (0.67 g) and 10% wt/wt Pd/C (0.175 g). After the catalyst was removed by filtration, the solvent was evaporated and the residue triturated with cold water. The tosylate salt (IV) was filtered and dried over P2O5 under vacuum, m.p. 125 .
(ii) BOC-Tyr(But)-D-Ala-OH (0.53 g) and Tos#Gly#-Phe-NH-i-Am (0.6 g) were dissolved in DMF (3 ml) and cooled in an ice-salt bath when HONSu (0.328 g) and DCCI (0.29 g) were added followed by NMM (0.131 g, 1.31 ml of a 10% wt/vol solution in DMF).
The reaction mixture was allowed to attain room temperature and stirred for 18 hrs when
DCU was filtered off and the solvent evaporated. The work up was followed as described for (III). The compound (V) was recrystallised from ethyl acetate/petroleum ether. Yield = (0.68 g, 77%) m.p. 180-182.
(e) L-Tyrosyl-D-alanylglycyl-L-phenylalanine-3-methylbutylamide (VI)
BOC-Tyr(But)-D-Ala-Gly-Phe-NH-i-Am (0.65 g) was treated at ambient temperature with 4M hydrogen chloride in ethyl acetate (5 ml) for 45 minutes and then the solvent was evaporated. The residue was triturated with diethyl ether and filtered (0.53 g).
Chromatography on a silica column (48cm x 2.5cm) with solvent system 7C gave a residue which was dissolved in 1M hydrochloric acid (15 ml) and lyophillized. yield = (0.4 g). m.p.
156-161", Rf7C = 0.4.
EXAMPLE 2
N-Methyl-L-tyrosyl-D-alanyl-glycyl-L-phenylalanine-3-methylbutylamide
This was prepared according to the following method:
WMFTyr Ala Gly Phe But BOC ONSu H OH But BOC But OH Tos H2 - - -NH i-Am BOO / NH i-Am H . - NH i-Am (a) N-Methyl-N-t-butyloxycarbonyl-O-t-butyl-L-tyrosyl-D-alanine
This depeptide was prepared (by the method of Example 1(a) ) by converting
N-Me-N-BOC-Tyr(But)-OH (2.5 g) to its ONSu active ester and then coupling to D-alanine (0.731 g) in the presence of TMG (0.954 g). The dipeptide was recrystallised from ethyl acetate/petroleum ether. yield = (2 g). m.p. 109-110 , Rf7D = 0.50.
(b) N-Methyl-N-t-butyloxycarbonyl-L-tyrosyl-D-alanylglycyl-L-phenylalanine-3methylbutylamide
This was prepared (by the method of Example 1(d)(ii) ) by coupling N-Me-N-BOC
Tyr(But)-D-Ala-OH (0.846 g) with Tos#Gly#-Phe-NH-isoamyl (0.928 g) in DMF using
DCCI (0.454 g) and HONSu (0.506 g) in the presence of NMM (0.202 g, 2.02 ml of a 10% wt/vol solution in DMF). After the work up a gum was obtained which solidifed on trituration with ice-water, yield = (1.2 g).
(c) N-Methyl-L-tyrosyl-D-alanylglycyl-L-phenylalanine-3-methylbutylamide
N-Me-N-BOC-Tyr(But)-D-Ala-Gly-Phe-NH isoamyl (0.6 g) was treated at ambient temperature with excess 4M hydrogen chloride in ethyl acetate for 40 minutes and then the solvent was evaporated. The residue was chromatographed on a silica column (45 cm x 2.5 cm) with solvent system 7C. The residue was lyophillized to yield a white solid (0.28 g), m.p. 90-94", Rf7B = 0.50.
The table sets out details of further compounds of Formula I which may be prepared by the methods of the above Examples or by other techniques well known in peptide chemistry, the Rf's having been determined using solvent systems 7B, 7C or 3A.
TABLE
Ex. Compound Rf m.p.
No.
3 H-Tyr-D-Ala-Gly-Phe-N(Me)i-amyl 7B: 0.4 159 4 Me-Tyr-D-Ala-Gly-Phe-N(Me)i-amyl 7B: 0.35 135 5 H-Tyr-D-Ala-Gly-Phe-NH(CH2)2Ph 7B: 0.4 150
6 Me-Tyr-D-Ala-Gly-Phe-NH(CH2)2Ph 7B: 0.4 122
7 H-Tyr-D-Ala-Gly-Phe-NH(CH2)3SMe 7C: 0.35 148
8 Me-Tyr-D-Ala-Gly-Phe-NH(CH2)3SMe 7C: 0.55 125 9 H-Tyr-D-Ala-Gly-Phe-NH(CH2)3Ph 7C: 0.2 138-140 10 Me-Tyr-D-Ala-Gly-Phe-NH(CH2)3Ph 7C: 0.62 124-131
13 Cpm-Tyr-D-Ala-Gly-Phe-NH i-amyl 7C: 0.5 1600 14 Allyl-Tyr-D-Ala-Gly-Phe-NH i-amyl 7C: 0.35
16 H-Tyr-D-Met-Gly-Phe-NH i-amyl 7B: 0.69 17 H-Tyr-D-Ala-Gly-Phe-NH Me 7B: 0.21 18 H-Tyr-D-Ala-Gly-Phe-N(i-amyl)2 19 Cpm-Tyr-D-Ala-Gly-Phe-NH (CH2)3SMe 20 H-Tyr-D-Ala-Gly-Phe-N(Me)(CH2)3SMe 21 Me-Tyr-D-Ala-Gly-Phe-N(Me)(CH2)3SMe 22 H-Tyr-D-Ala-Gly-Phe-N(Me)(CH2)3Ph 23 Cpm-Tyr-D-Ala-Gly-Phe-NH(CH2)3Ph 24 H-Tyr-D-Ala-Gly-Phe-NH CH(CH2OH)(CH2)2SMe 25 H-Tyr-D-Ala-Gly-Phe-NH CHMe(CH2)2SMe 26 H-Tyr-D-Ala-Gly-Phe-NH CHMeCH2CHMe2 27 H-Tyr-Aib-Gly-Phe-NH(CH2)3SMe 28 H-Tyr-Aib-Gly-Phe-NH i-amyl 29 Me-Tyr-D-Ala-Gly-MePhe-N(Me) i-amyl 30 H-Tyr-Aib-Gly-Phe-N H(C H2)2Ph 31 Me,-Tyr-D-Ala-Gly-Phe-NH i-amyl 32 Ph(CH2)2-Tyr-D-Ala-Gly-Phe-NH i-amyl 33 Propargyl-Tyr-D-Ala-Gly-Phe-NH i-amyl 34 H-Tyr-D-Ala-Gly-Phe-NH n-Pr 35 H-Tyr-D-Ala-Gly-Phe-NH n-octyl 36 H-Tyr-D-Ala-Gly-Phe-NH cyclopentyl
38 H-Tyr-D-Ser-Gly-Phe-NH i-amyl 39 H-Tyr-D-Ser(O-Me)-Gly-Phe-NH i-amyl
42 H-Tyr-D-Phe-Gly-Phe-NH i-amyl 43 H-Tyr-D-Ala-Gly-Phe-NH CH(CH,OH)i-butyl 44 Me-Tyr-D-Ser-Gly-MePhe-NH i-amyl
Abu = D-a-aminobutyric acid m.p.'s are of hydrochlorides
Cpm = cyclopropylmethyl Aib = a-aminoisobutyric acid
In the above mentioned test method of Henderson et al male albino mice (OLA MFI strain) are killed by a blow on the head and the vasa deferentia removed and set up in an isolated organ bath of 22 ml volume. A 'twitch' response is produced by low frequency ((1.1 Hz) stimulation with 0.1 msec rectiliniar pulses. The response is depressed by a large number of different pharmacologically active agents (local anaesthetics. smooth muscle depressants, adrenergic neuron blocking agents. presynaptic α-receptor stimulants, -stimulants and narcotic agonists) but it is possible to differentiate between depression of twitch produced by narcotic agonists and depression produced by other mechanisms. by repeating the test in the presence of a narcotic antagonist naloxone [The test has been shown to be an extremely specific method of detecting narcotic agonist and antagonist activity (Hughes J, Kosterlitz H, Leslie F M. Brit. J. Pharmacol 51. 139-140.)].
A test compound is dissolved in distilled water to produce a stock solution of concentration l mg/ml. Serial dilutions are carried out using Krebs solution to produce concentrations of 10 tig, l Iig and o.l Fg/ml. The compound is tested by adding between 0.1-0.3 ml of the solutions to the organ bath. A dose response curve is then drawn and compared with that for dihydromorphine. In this test H-Tyr-D-Ala-Gly-Phe-NH i-Am possessed approximately 11 times the activity of dihydromorphine calculated on a weight basis whilst Me-Tvr-D-Ala-Gly-Phe-NH i-Am has approximately 9 times the activity.
The compounds of the invention have also been screened for antidiarrhoeal activity according to the method of Boura. A.L.A., Fitzgerald. A.E., Brit. J. Pharmac., 26, 307 (1966). In this test H-Tyr-D-Ala-Gly-Phe-NH i-Am when administered i.v. to mice had an
ED50 of 4.7 mg/Kg whilst Me-Tyr-D-Ala-Gly-Phe-NH i-Am had an ED50 of 0.39 mg/Kg.
The therapeutic compositions may be in a form suitable for oral administration or in a form suitable for parenteral administration. Such oral compositions may take the form of capsules. tablets. granules or liquid preparations such as elixirs, syrups or suspensions.
Compositions intended for parenteral administration may be in the form if sterile preparations such as solutions in water or salinc.
For the purposes of convenience of accuracv of dosing the compositions are advantageously employed in a unit dosage form.
Claims (17)
1. Compounds of the formula (I)
wherein R1 is hydrogen, alkyl C1-4, alkenyl C3-5, propargyl, cycloalkyl C3-7 methyl or phenyl-alkyl
C1-3;
R2 is hydrogen or alkyl C1-4:
R8 is alkyl C1-10, cycloalkyl C3-6, -CH(CH2OH) alkyl C1-5, cycloalkyl C3-6 alkyl C1-5, phenyl, phenyl-alkyl C1-5, hydrogen, CpH2pXCqH2q+1 (where p is 2-6, q is 1-5 and X is oxygen or sulphur) or -CH(CH2OH)(CH2)2SMe;
R9 is hydrogen, alkyl C1-10, phenyl or phenyl-alkyl C1-6;
or NR8R9 may be pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, which groups may be substituted by alkyl C1-3 or phenyl;
B is a D-serine or D-threonine radical or an alkyl C1-4 ether thereof, or a D-proline,
D-tryptophan, D-phenylalanine or D-methionine radical or the group -NH-CR6R7-CO (where R6 is alkyl C1-5 and R7 is hydrogen or methyl) the group having the D-configuration or the group
(where n is 2-5); the group Phe may optionally be N-substituted by methyl; and the acid addition salts thereof.
2. Compounds of the formula:
wherein
R1 is hydrogen, alkyl C1-4, alkenyl C3-5, propargyl, or cycloalkyl C3-7 methyl;
R2 is hydrogen or alkyl C1-4;
R8 is alkyl C3-6 or (CH2)3SCH3;
R9 is hydrogen;
B is a D-serine, D-threonine, D-proline, D-phenylalanine or D-methionine radical or the group -NH-CR6R7-CO (where R6 is alkyl C1-5 and R7 is hydrogen or methyl) the group having the D-configuration or the group
(where n is 2-5); and the acid addition salts thereof.
3. Compounds of the formula:
wherein
R1 is hydrogen,alkyl C1-4, alkenyl C3-5, propargyl, cycloalkyl C3-7 methyl or phenyl-alkyl
C1-3;
R2 is hydrogen or alkyl C1-4;
B is a D-serine or D-threonine residue or an alkyl C1.4 ether thereof, or a D-proline,
D-phenylalanine or D-methionine radical or the group -NH-CR6R7-Co (where R6 is alkyl C1.5 and R7 is hydrogen or methyl) the group having the D-configuration or the group
(where n is 2-5);
R8 is alkyl C1-10, cycloalkyl C3-6, -CH(CH2OH)alkyl C1-5, cycloalkyl C3-6 alkyl C1-5, phenyl, phenyl-alkyl C1-5, -CpH2pXCqH2q+1 (where p is 2-6, q is 1-5, and X is oxygen or sulphur) or -CH(CH2OH)(CH2)2SMe;
R9 is hydrogen, alkyl C1-10, phenyl or phenyl-alkyl C1-6; or
NR8R9 may be pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, which groups may be substituted by alkyl C1-3; and the acid addition salts thereof.
4. Compounds of the formula
wherein R' is hydrogen, methyl, cyclopropylmethyl, cyclobutylmethyl, allyl, dimethylallyl or phenethyl; R2 is hydrogen or methyl;
B is a D-alanine, D-leucine, D-valine or D-a-aminobutyric acid, a-aminoisobutyric acid radical or the group (where n is 2-5);
R is alkyl C1-8, phenyl, phenylalkyl C1-5 or -CpH2qXCqH2q+1 (where p is 3-6, q is 1-4 and
X is oxygen or sulphur);
R9 is hydrogen, alkyl C1.5, phenyl or phenyl-alkyl C1.5; and the acid addition salts thereof.
5. Compounds of the formula
wherein
R1 is hydrogen, alkyl C1-4, allyl, propargyl, or benzyl;
R2 is hydrogen or alkyl C1-4; B is a D-alanine, D-α-alkyl C1-5 alanine, D-valine, D-norvaline, D-leucine, D-isoleucine,
D-norleucine, D-proline or D-tryptophan radical; R8 is hydrogen or alkyl C1-10; R9 is hydrogen or alkyl C1-10; or NR8R9 may be pyrrolidino, piperidino or morpholino; the group Phe may optionally be N-substituted by alkyl C1-10; and the acid addition salts thereof.
6. L-Tyrosyl-D-alanylglycyl-L-phenylalanine-3-methylbutylamide
7. L-Tyrosyl-D-alanylglycyl-L-phenylalanine-3-thiomethylpropylamide
8. N-Methyl-L-tyrosyl-D-alanylglycyl-L-phenylalanine-3-methylbutylamide
9. N-Methyl-L-tyrosyl-D-alanylglycyl-L-phenylalanine-3-thiomethylpropylamide
10. L-Tyrosyl-D-alanylglycyl-L-phenylalanine-N'-methyl-N'-3-methylbutylamide
11. L-Tyrosyl-D-a-anylglycyl-L-phenylalanine N'-methyl-N'-3-thiomethylpropylamide
12. N-Methyl-L-tyrosyl-D-alanylglycyl-L-phenylalanine-N'-methyl-N'-3- methylbutylamide
13. N-Methyl-L-tyrosyl-D-alanylglycyl-L-phenylalanine-N'-methyl-N'-3thiomethylpropylamide
14. A compound of Formula 1 as defined in claim 1, substantially as herein described in any one of the Examples.
15. A process for the preparation of a compound according to any one of claims 1 to 5, in which process a compound of the formula
Y-M1-OH 11 where M, is an amino-acid or peptide residue and Y is a N-protecting group, is condensed with a compound of the formula H-M2-Q III where M2 is an amino-acid or peptide residue and Q is a carboxyl protecting group. the compound 11 being optionally activated. followed by deprotection of the resultant product.
16. A compound according to any one of claims 1 to 5 when prepared by a method according to claim 15.
17. A therapeutic composition comprising a compound as claimed in any one of claims
I to 14 or claim 16. or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaccutically acceptable diluent or carrier.
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB31194/76A GB1577115A (en) | 1976-07-27 | 1976-07-27 | Container closure units |
| DK326477A DK326477A (en) | 1976-07-27 | 1977-07-18 | CHEMICAL COMPOUNDS AND PROCEDURE FOR PREPARING THE SAME |
| DE19772732451 DE2732451A1 (en) | 1976-07-27 | 1977-07-18 | Peptide morphine agonists - for use as analgesics, sedatives, antitussives, etc. |
| SE7708486A SE7708486L (en) | 1976-07-27 | 1977-07-22 | PEPTIDES AND PROCEDURES FOR THEIR PREPARATION |
| BE6046093A BE857138A (en) | 1976-07-27 | 1977-07-25 | PEPTIDIC DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC COMPOSITIONS CONTAINING THESE COMPOUNDS |
| LU77838A LU77838A1 (en) | 1976-07-27 | 1977-07-25 | |
| AU27279/77A AU2727977A (en) | 1976-07-27 | 1977-07-25 | Peptides |
| NL7708225A NL7708225A (en) | 1976-07-27 | 1977-07-25 | PROCESS FOR THE PREPARATION OF PEPTIDES. |
| ZA00774479A ZA774479B (en) | 1976-07-27 | 1977-07-25 | Peptides,processes for their preparation and compositions containing same |
| JP8914177A JPS5325537A (en) | 1976-07-27 | 1977-07-25 | Compound |
| FR7722766A FR2359817A1 (en) | 1976-07-27 | 1977-07-25 | Peptide cpds. contg. tyrosine, glycine, phenylalanine and d-amino acid - local anaesthetics, smooth muscle relaxants, adrenergic neutron blockers, beta-stimulants etc. |
| NZ184735A NZ184735A (en) | 1976-07-27 | 1977-07-25 | Peptides and pharmaceutical compositions |
| US06/074,408 US4254106A (en) | 1976-01-26 | 1979-09-10 | Biologically active amides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB31194/76A GB1577115A (en) | 1976-07-27 | 1976-07-27 | Container closure units |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1577115A true GB1577115A (en) | 1980-10-22 |
Family
ID=10319414
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB31194/76A Expired GB1577115A (en) | 1976-01-26 | 1976-07-27 | Container closure units |
Country Status (3)
| Country | Link |
|---|---|
| BE (1) | BE857138A (en) |
| GB (1) | GB1577115A (en) |
| ZA (1) | ZA774479B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0031567A2 (en) * | 1979-12-27 | 1981-07-08 | Takeda Chemical Industries, Ltd. | Tetrapeptidesemicarbazide derivatives and their production and use |
| EP0109142A2 (en) * | 1982-10-18 | 1984-05-23 | Imperial Chemical Industries Plc | Peptide and pseudopeptide derivatives |
| US4459225A (en) * | 1979-08-22 | 1984-07-10 | Hoechst Aktiengesellschaft | Peptide amides and process for their manufacture |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1604850A (en) * | 1977-11-24 | 1981-12-16 | Wellcome Found | Biologically active peptides |
| US4221682A (en) * | 1979-08-06 | 1980-09-09 | American Home Products Corporation | Tetrapeptides having analgesic activity |
| US4265808A (en) * | 1979-12-17 | 1981-05-05 | Eli Lilly And Company | Pharmacologically active peptides |
| US4283330A (en) * | 1979-12-17 | 1981-08-11 | Eli Lilly And Company | Pharmacologically active peptides |
| US4283329A (en) * | 1979-12-17 | 1981-08-11 | Eli Lilly And Company | Pharmacologically active peptides |
| US4251439A (en) * | 1979-12-17 | 1981-02-17 | Eli Lilly And Company | Pharmacologically active peptides |
| US4333873A (en) | 1979-12-17 | 1982-06-08 | Eli Lilly And Company | Pharmacologically active peptides |
| US4322340A (en) * | 1980-10-20 | 1982-03-30 | Eli Lilly And Company | Pharmacologically active peptides |
| US4322339A (en) * | 1980-10-20 | 1982-03-30 | Eli Lilly And Company | Pharmacologically active peptides |
-
1976
- 1976-07-27 GB GB31194/76A patent/GB1577115A/en not_active Expired
-
1977
- 1977-07-25 ZA ZA00774479A patent/ZA774479B/en unknown
- 1977-07-25 BE BE6046093A patent/BE857138A/en unknown
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4459225A (en) * | 1979-08-22 | 1984-07-10 | Hoechst Aktiengesellschaft | Peptide amides and process for their manufacture |
| EP0031567A2 (en) * | 1979-12-27 | 1981-07-08 | Takeda Chemical Industries, Ltd. | Tetrapeptidesemicarbazide derivatives and their production and use |
| EP0031567A3 (en) * | 1979-12-27 | 1981-11-04 | Takeda Chemical Industries, Ltd. | Tetrapeptidesemicarbazide derivatives and their production and use |
| EP0109142A2 (en) * | 1982-10-18 | 1984-05-23 | Imperial Chemical Industries Plc | Peptide and pseudopeptide derivatives |
| EP0109142A3 (en) * | 1982-10-18 | 1985-08-21 | Imperial Chemical Industries Plc | Peptide and pseudopeptide derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA774479B (en) | 1978-06-28 |
| BE857138A (en) | 1978-01-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU633872B2 (en) | Glycine derivatives | |
| Lipkowski et al. | Double-enkephalins—synthesis, activity on guinea-pig ileum, and analgesic effect | |
| US3832337A (en) | Peptide enzyme inhibitors | |
| US4472305A (en) | Hexapeptide amides | |
| NZ505183A (en) | KOR agonists that are synthetic tetrapeptides with D-isomer amino acids exhibiting high affinity for the KOR versus the MOR and not penetrating the brain | |
| FI70228C (en) | FRAMEWORK FOR FRAMSTAELLNING AV EN ENKEFALIN ANALOG PEPTID | |
| US4178371A (en) | Tetrapeptide derivatives | |
| US4127534A (en) | Novel tripeptides, intermediates therefor and pharmaceutical compositions and methods employing said tripeptides | |
| GB1577115A (en) | Container closure units | |
| US4322339A (en) | Pharmacologically active peptides | |
| US4254106A (en) | Biologically active amides | |
| US4322340A (en) | Pharmacologically active peptides | |
| HU182866B (en) | Process for preparing new tetrapeptide derivatives | |
| KR840001668B1 (en) | Process for the preparation of peptides | |
| CA1142514A (en) | Pharmacologically active peptides | |
| US4309343A (en) | Pharmacologically active peptides | |
| KR840001720B1 (en) | Process for the preparation of peptides | |
| US4448717A (en) | Pharmacologically active peptides | |
| HU186375B (en) | Process for the preparation of biologically active encephalina derivatives | |
| DE2732451A1 (en) | Peptide morphine agonists - for use as analgesics, sedatives, antitussives, etc. | |
| US4127533A (en) | Novel octapeptides, intermediates therefor, and compositions and methods employing said octapeptides | |
| US6051685A (en) | Peptide derivatives | |
| EP0755942B1 (en) | N-amidino dermorphin derivative | |
| US4127540A (en) | Novel derivatives of δ-endorphins, intermediates therefor, and compositions and methods employing said derivatives | |
| US4473497A (en) | Pharmacologically active peptides |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed | ||
| PCNP | Patent ceased through non-payment of renewal fee |