New amiodorone peptides, the method of production thereof, and pharmaceutical composition

 

(57) Abstract:

Describes the new amiodorone peptides of the formula I X-R1-R2-R3-R4-N(Z)-Y, as well as their salts, derivatives and analogues, where X is hydrogen; R1- Tyr; R2- D-Ala or D-Arg; R3- Phe (p-F); R4- Phe or Phe (p-F); Y and Z are H. the New compounds possess analgesic activity of peripheral activity and the selectivity to the subtype of opioid receptors. Also describes the method of production thereof, pharmaceutical composition. 3 C. and 10 C.p. f-crystals, 5 Il., table 1.

The present invention relates to opioiddependent peptide compounds. More specifically, it relates to opioiddependent peptide compounds, which possess analgesic activity of peripheral activity and the selectivity to the subtype of opioid receptors.

Background of the invention

Many endogenous peptides mammals and amphibians are associated with specific opioid receptors and cause analgesic reaction similar to the reaction caused by the classical narcotic opiates. It was shown that in the higher animals at the same time there are many different types of opioid receptors. For example, see W. Ma is different receptors. First, discovers a selective affinity to encephalopathy peptides. Second , has a high selectivity to morphine and other polycyclic alkaloids. Third, k, has an equal affinity to any group of the above ligands and preferential affinity to dynorphin. In analgesic effects, seems to be mainly involved receptors. Obviously, receptors associated with behavioral effects, though - and k-receptors can also mediate analgesia.

Each opioid receptor in the interaction with opiate cause specific biological reaction that is unique to this type of receptor. When the opiates activate more than one receptor, then spent the biological response of each receptor that gives side effects. The lower the specificity and selectivity of opiate, the greater the likelihood of multiple side effects after injection of the opiate.

In previous studies, opiates, opioid peptides and their analogues were not detected or were detected limited selectivity to the type of receptor or receptors with which they are associated.

Opiates can cause serious side effects, and sometimes side e is dedicated tool, the acquisition of physical dependence on narcotic drugs and the withdrawal syndrome, are caused by nonspecific interactions with opiates receptors of the Central nervous system. Cm. K. Budd, in International Encyclopedia of Pharmacology and Therapeutics; N. E. Williams and H. Wilkinson, Eds., Pergammon: (Oxford), 112, p. 51 (1983). On this basis it should be expected that opioid analgesics acting only on the opioid receptors of the peripheral nervous system, will not cause the same undesirable side effects which cause opioid analgesics Central action.

One of the few currently known classes (compounds) with periodic analgesic effect, are non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen and Ketorolac. These substances do not interact with opioid receptors, but it is known that they inhibit cyclooxygenase, and inhibit the synthesis of prostaglandins. These weak analgesics do not have side effects associated with the receptors of the Central nervous system, however, can cause other side effects such as ulceration in the gastrointestinal tract.

It was assumed that the non-polar peptides are more easily penetrate into C is x reported, the peptide TAPP (H-Tyr-D-Ala-Phe-Phe-NH2possesses antinociceptive (analgesic) properties of both peripheral and Central actions (P. Schiller et al. Proceedings of the 20th European Peptide Symposium, 1988). In contrast, in the present invention it was shown that this tetrapeptide has any kind of Central action even at doses of 100 mg/kg

The aim of the present invention to provide opiatopodobnyh peptide compounds peripheral actions, which do not have undesirable side effects associated with conventional analgesics peripheral actions. Another objective of the invention to provide peptides that selectively bind with opioid receptors.

Brief description of the invention

The present invention relates to new peptide compounds peripheral actions, which are selective K-opioid receptors, which can be represented by the formula I

< / BR>
and their salts, derivatives and analogues,

where R1- Tight or 2'6'-dimethylthiazol, or its derivative, or analogue;

R2- D-Ala or D-Arg;

R3- Phe (p-F);

R4- Phe or Phe(p-F);

X - H or C1-6-alkyl;

Y and Z tositsa to pharmaceutical compositions, including the compounds of formula (I) in combination with a pharmaceutically acceptable carrier and/or the second therapeutically active agent.

In the following aspect, the present invention relates to a method of treatment of pain, involving the administration to a mammal in need of such introduction of a pharmaceutically effective amount of the compounds of formula (I).

In another aspect, the present invention relates to the use of compounds of formula (I) to obtain a painkiller drug.

Brief description of drawings

Fig. 1, 2 and 4 illustrate the inhibitory activity of the compounds of the present invention in two different tests conducted using hot platform.

Fig. 3 illustrates the inhibitory effect of H-Tyr-D-Ala-Phe-Phe-NH2in the test using "hot platform.

Fig. 5 illustrates the inhibitory activity of the compounds of the present invention in the test for the dramatic movement of the tail.

Description of the invention

In the description and the claims, use the following standard abbreviations:

Ala - alanine

Arg - arginine

Phe - phenylalanine

Ser - serine

Tyr - tyrosine

TAPP - H-Tyr-D-Ala-Phe-

HOBT IS N-hydroxybenzotriazol

BOP - benzotriazolyl-N-oxy-Tris(dimethylamino) fosfodiesterasa

DMF - dimethylformamide

TFA - triperoxonane acid

tBU is tert-butyl

Pmc - 2,2,5,7,8-pentamethylchroman-6-sulfonyl

FMOC - 9-fluorenylmethoxycarbonyl

PBQ - phenyl-para-benzoquinone.

Value: "ED50"presented in the table for test PBQ-induced convulsions, means the dose of a drug which causes a decrease in the number of seizures by 50% compared with control. The value of "Ki"are presented in table 1 for the analysis of binding indicates the inhibition constant obtained using a known ligand DAMGO for receptor and ligand DADLE for-receptor.

Ki/Ki" means the value used for selectivity estimation. This value represents the ratio of affinely binding of opioid peptides and receptors.

Compounds of the present invention are compounds of the formula I

< / BR>
and also their salts, derivatives and analogues.

X represents H or methyl, preferably H;

R1is Tyr or 2'6'-dimethylthiazol, preferably Tyr, alpha-amino group dstanley methyl;

R2is D-Ala or D-Arg, preferably D-Ala;

R3is Phe(p-F);

R4is Phe or Phe(p-F), preferably Phe;

Y and Z independently represent H, aralkyl, such as benzyl, or C1-6-alkyl, such as methyl, preferably, Y and Z were both N.

The compounds of the present invention are the following compounds, but are not limited to:

Connection # 1B H-Tyr-D-Ala-Phe(p-F)-Phe(p-F)-NH2;

Connection # 1C H-Tyr-D-Ala-Phe(p-F)-Phe-NH2;

Connection # 2B H-Tyr-D-Arg-Phe(p-F)-Phe(p-F)-NH2;

Connection # 2C H-Tyr-D-Arg-Phe(p-F)-Phe-NH2.

In a preferred embodiment, compounds of the present invention are selected from the group including

Connection # 1C H-Tyr-D-Ala-Phe(p-F)-Phe-NH2;

Connection # 2C H-Tyr-D-Arg-Phe(p-F)-Phe-NH2.

In a more preferred embodiment, the compound of the present invention is

Connection # 1C H-Tyr-D-Ala-Phe(p-F)-Phe-NH2.

In opioid peptide compounds tyrosine can be replaced by an amino acid derivative of 2'6'-dimethylthiazol (Dmt). Experiments have shown that the replacement of tyrosine by Dmt at R1the first amino acid residue of General formula I increases the efficiency of opioiddependent contains Dmt at R1. This replacement leads to a corresponding change in the attitude of the constants of inhibition of binding, reflecting the increase in selectivity for receptors.

Opioid activity of the peptides was analyzed in vitro using drug longitudinal muscle of the ileum of the Guinea pig, and their analgesic activity was determined using the in vivo model PBQ-induced convulsions (peripheral activity) and two tests using hot platform (Central activity). Analgesic activity of the compounds of the present invention were evaluated in the test for sudden movements ("otdeleniye") tail. Test for sudden movements of the tail was conducted to assess the Central analgesic action of the test compounds. Comparison of the activity of the compounds of the invention in experiments with induced seizures using "hot" platform and in tests on the dramatic movement of the tail showed that the analgesic effects were mediated primarily by receptors of the peripheral nervous system. In the test with induced convulsions was observed a high degree of peripheral analgesia, whereas in tests using hot platform test and the Chi (PBQ-phenylpropanamine) is a criterion in the assessment as peripheral, and Central analgesia. Scheme of the experiment described in the work of Sigmund et al., Proc. Soc. Exp. Biol. Med., 95, p. 729 (1957), which is given here by reference. Central analgesia was determined by the inhibition of the reaction in mice in the test using the hot platform. Description of the experiment see the work of G. Wolfe and A. MacDonald, J. Pharmacol. Exp. Ther., 80, p. 300 (1944), which is given here by reference. Tests to determine the affinity of binding - and-opioid receptors, as well as the test using GPI were described in Schiller et al., Biophys. Res. Commun., 85, p. 1322 (1965), which is given here by reference.

Compounds of the present invention can be obtained by methods well known in the practice of peptide chemistry. For example, see Principle of Peptide synthesis, M. Bodansky, Springer-Verlag, Berlin, Heidelberg, New York, Tokyo 1984 or The Peptides, Analysys, Synthesis, Biology, edited by Erhard Gross and Johaness Meienhofer, Academic Press 1979.

Compounds of the present invention were obtained by solid-phase synthesis, as described below, in accordance with the methods commonly used for the synthesis of peptides. Commercially available para-forfinally (Phe(p-F) used at an appropriate stage of the synthesis. 2'6'-dimethylthiazol can be used in the synthesis and received Svea can be obtained in the usual way by reaction with the appropriate acid. Suitable acid additive salts can be obtained using such acids as hydrochloric, Hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, oxyphenylbutazone, tartaric, oxalic, metasulfuron, and other suitable acids, known to specialists.

The present invention also relates to pharmaceutical compositions. Suitable compositions contain a pharmaceutically effective amount of the compounds of the present invention or their pharmaceutically acceptable salts in a mixture with pharmaceutically acceptable carriers or additives. A therapeutically effective amount of the peptide of the present invention in combination with pharmaceutically acceptable carrier (i.e., magnesium carbonate or lactose) can be used to obtain a therapeutic compound, such as

(i) pills, tablets, capsules or liquid for oral administration to a patient;

(ii) the liquid or ointment for administration by inhalation, transdermally, intranasally, rectally or under the tongue;

(iii) solution for intravenous, parenteral, subcutaneous or intraperitoneal injection;

(iv) not oral or parenteral drug prolonged action. Prov.ka. This method provides for the introduction of pharmaceutically effective amount of the peptide of formula I or its pharmaceutically suitable salt or composition of one of the traditional ways, i.e., oral, parenteral, percutaneous go through mucous membranes. As prolonged drug action using biologically compatible polymer or by delivering targeted at the right of the target tissue using micelles, gels and liposomes. The peptides can be administered to the human in a dose of from 0.01 to 100 mg/kg, preferably from 0.05 to 20 mg/kg and most preferably from 0.1 to 1 g.

The following examples are provided to better describe the invention. These examples are only for illustrative purposes and should not be construed as a limitation of the invention.

Example 1

Obtaining 1C H-Tyr-D-Ala-Phe(p-F)-Phe-NH2< / BR>
The synthetic peptide was obtained using the resin (polymer carrier) Knorr. Used amino acids had Fmoc-substituted alpha-amino group and tBU-protected side chain of tyrosine. Dimethylformamide, used at the stage of accession, did not contain dimethylamine. DMF used at the stage of washing, and TFA were organic (Biograde). For stud is Writely were ACS (spectrophotometric) pure and was used without further purification.

Solid phase synthesis was carried out manually on the gel with the workload 0.84 mmol/g Condensation of peptides was performed using 1.5-2 equivalent (each) Fmoc-amino acid, HOBT and BOP in DMF for 3-24 hours at room temperature. Stage for removal of Fmoc protection of alpha-amino groups were carried out using 20% (v/v) piperidine in DMF for 25 minutes. Cleavage of the peptide and removing the protection of the side chains was carried out by treatment with TFA/CH2Cl2/anisole. Peptide polymer carrier was treated with TFA for two periods of 90 minutes at room temperature in a nitrogen atmosphere. After laundering CH2Cl2and drying the residue was treated with ethyl ether, the precipitate was filtered and dried under vacuum.

The crude peptide was purified by HPLC on a column of C1810-15 300A with reversed phase, using a gradient elution is 0.06% TFA/H2O and 0.06% TFA/acetonitrile. Monitoring was carried out at 220 nm. Pure fractions were combined and liofilizirovanny. The purified material was turned in his cleaners containing hydrochloride salt with obtaining pure target compound:

The same method were synthesized following peptides:

1A H-Tyr-D-Ala-Phe-Phe-NH2< / BR>
1B H-Tyr-D-Ala-Phe(p-F)-Phe(p-l obtained using Knorr. Used amino acids had Fmoc-protected alpha-amino group, and Pmc-protected side chain of D-arginine, and tBU-protected side chain of tyrosine. Dimethylformamide, used at the stage of accession, did not contain dimethylamine. DMF used at the stage of washing, and TFA were organic (Biograde). For the stage of purification was used USP-purified H2O and acetonitrile, purified by HPLC. All remaining solvents were ACS-pure and was used as such without any treatment.

Solid phase synthesis was carried out manually on the polymer carrier with load 0.84 mmol/g Condensation of peptides was performed using 2 equivalent (each): Fmoc-amino acid, HOBT and BOP in DMF for 2 to 5 hours at room temperature. The stage of removal of the Fmoc protection of alpha-amino groups were carried out using 20% (v/v) (volume percent) of piperidine in DMF for 25 minutes. Cleavage of the peptide and removing the protection of the side chains was carried out by treatment with TFA/CH2Cl2/anisole. Peptide polymer was treated with TFA for two periods of 90 minutes at room temperature in a nitrogen atmosphere. After washing CH2Cl2and drying the residue was treated with ethyl is attended by HPLC on a column of C1810-15 300A with reversed phase using a gradient elution is 0.06% TFA/H2O and 0.06% TFA/acetonitrile. Monitoring was carried out at 220 nm. Pure fractions were combined and liofilizirovanny.

In the same way were synthesized following peptides:

2A H-Tyr-D-Arg-Phe-Phe-NH2< / BR>
2B H-Tyr-D-Arg-Phe(p-F)-Phe(p-F)-NH2.

Example 3

Analysis of the binding of radioactive labeled ligand

Preparation of membranes

Male rats Sprague-Dawley weighing from 350 to 450 g were killed by inhalation of CO2. Rats were decapitated, and the brain without cerebellum was removed, placed in ice (cooled to the temperature of ice) saline and then homogenized in 50 mM cold (the temperature of the ice) Tris buffer (pH of 7.4) (10 ml/brain). Membranes were centrifuged at 14000 rpm for 30 minutes at 4oC. Precipitates after centrifugation resuspendable in ice-cold 50 mM Tris buffer (pH 7,4), approximately in the ratio of 6 ml/brain, and placed in storage at -78oC until use. Quantification of protein in the homogenate of the brain was performed using a commercially available kit for the analysis of proteins (Bio-Rad).

Inhibition of radioligand

(3H)-DAMGO and (3H)-DAGLE were ippany and serially diluted control compound were incubated for 1 hour at 22oC. Nonspecific binding was determined using a 500-fold excess of its ligand in the presence of a radioactive label and membranes. The free ligand was separated from bound by filtering through paper Whatman GF/B (pre-soaked in 1% aqueous solution of polyethylenimine) and washed in 500 mM ice-cold buffer, pH 7,4, using a cell harvester cells Brandel. The filters were dried and radioactivity was counted in a 24-hole tablet for micrometrology in the presence of 500 ml of scintillator per well. Radioactivity was measured by means of a counter Wallac 1450 Microbeta.

Ki(the inhibition constants for the various compounds were determined on the basis of the IC50the equation of Cheng and Prusoff. The results of the analysis on the binding systematized in the table.

The activity of peptide compounds in relation to the receptor was determined in a test using ileum of the Guinea pig (GPI) (drug longitudinal muscles) according to the method described by Schiller et al., Biophys. Res, Communn., 85, p. 1322 (1975). The results of the activity systematized in the table.

Example 4

Test using "hot platform" (measurement of analgesic activity was carried out at 55oC.

Mice was done subcutaneous injection of the compound (or a standard connection, or environment) with a volume of injection, equivalent to 0.1 ml/10 g R. C. (10 ml/kg).

Mice were individually assessed by reaction time on the hot platform. The temperature of the hot platform (Sorel, model DS37) was 55oC. The mice were observed for signs of discomfort, such as licking or twitching paws, attempting maintenance (jump off platform) or jitter. Reaction time was recorded, when I had some of these symptoms, and expressed in "seconds". Each mouse was observed for a maximum period of 30 seconds to prevent tissue damage paws.

In each case, the registration time average response time in the control group were multiplied by 1.5. The reaction time of each test mouse was compared with the average control x 1.5". If the response time was less than the average control x 1.5", it is believed that the mouse analgesic effect is absent. If the reaction time was higher than the average control x 1.5", believed that the analgesic effect is. The percentage analgesic activity of a compound for the time of the test was determined by the number analiziropany (not sensitive to pain) mice in the group. If the percent is

Example 5

Test by inducing cramps

The test was performed on male mouse CD # 1 weighing from 18 to 22, the Mice were weighed and marked. These mice were injected with intraperitoneal (intraperitoneal) a 0.02% solution of finishinga in the amount of 0.3 ml/20 g weight. Convulsions, which appeared during the 15 minute period of time after the injection were counted. Finishined were subcutaneously injected with with time intervals of 5, 20 or 60 minutes after administration of the compound (or environment, or standard connections).

0.02% solution of finishinga (2-phenyl-1,4-benzoquinone (Sigma)) was prepared as follows. 20 mg finishinga was dissolved in 5 ml of 90% ethanol (Sigma, reagent, alcohol). Dissolved finishined was slowly added to 95 ml of warm (not boiling) distilled water with constant shaking. The solution finishinga was kept for 2 hours before use and in all cases in environment, protected from light. Every day for the test was preparing a new solution.

The results of systematic experiments in the table. You can see that the peptide compounds of the present invention, if one or both of R3or R4imagine Phe (p-F), show higher selectivity for the opioid the production of the receptor, as defined in the test using GPI. In addition, the compounds of the present invention show higher peripheral analgesic activity, as was shown in the test with induced convulsions.

Example 6

Test using hot platform (measurement of analgesic activity was carried out at 58oC.

For this test used a male mouse NMRI weighing from 20 to 25, Mice were weighed, marked and divided into groups of 6.

Mice was done subcutaneous injection of the compound (or a standard connection, or environment) when the volume of injection, equivalent to 0.1 ml/10 g R. C. (10 ml/kg).

Evaluation of the reaction time in mice on a hot platform was made individually for each mouse. The temperature of the hot platform (TCP, Inc; model 35-0) was 58oC. mice showed signs of discomfort, such as licking or shaking paws, attempting maintenance (off platform) or jitter. Reaction time was recorded when we received one of these symptoms, and expressed in "seconds". Each mouse was observed for a maximum period of 20 seconds to prevent tissue damage paws.

It was believed that the connection has analgesics is th analysis), sigma slot) contrast response time of the control group.

The results are shown in Fig. 4.

Example 7

Test for sudden movements of the tail

To implement this test used of male mice NMRI weighing from 20 to 25, the Mice were weighed, marked and divided into groups of 6.

Mice were administered subcutaneous injections of compounds (or a standard environment with the volume of injection, equivalent to 0.1/10, R. C. (10 ml/kg). Mice were individually assessed on the reaction time in the test for sudden movements of the tail. The latent period of time before the dramatic movement of the tail was measured at the moment when the adjustable rheostat light beam was focused on the tip of the tail (TCP Inc. Model 33). Each mouse was observed for a maximum of 10 seconds to prevent tissue damage.

The connection was considered to be analgesic, if the reaction time was significantly different (p<05, two-factor ANOVA (analysis of variance), Sigma Stat) on reaction time for the control group.

The results are presented in Fig. 5.

1. New amiodorone peptides of the formula I

< / BR>
as well as its salts, derivatives and analogues,

where X is hydrogen;

R1- Tyr;

R2- D-Ala or D-Arg;

R3- Phe (p-F);

R

3. Connection on p. 1, where R2presents D-Arg.

4. Connection on p. 1, where R4presents Phe.

5. Connection on p. 4, where R2presents D-Ala.

6. Connection on p. 4, where R2presents D-Arg.

7. Connection on p. 1, representing

H - Tyr - D - Ala - Phe (p-F) - Phe (p-F) - NH2.

8. Connection on p. 1, representing

H - Tyr - D - Ala - Phe (p-F) - Phe - NH2.

9. Connection on p. 1, representing

H - Tyr - D - Arg - Phe (p-F) - Phe (p-F) - NH2.

10. Connection on p. 1, representing

H - Tyr - D - Arg - Phe (p-F) - Phe - NH2.

11. Pharmaceutical composition having analgesic activity, comprising an effective amount of a compound according to any one of paragraphs.1 - 10 in a mixture with a pharmaceutically acceptable carrier.

12. Compounds according to any one of paragraphs.1 - 10 useful for the manufacture of the drug, effective for pain relief.

13. A method of obtaining a connection on p. 1 by solid-phase synthesis.

Priority points:

18.08.95 on PP.7 - 11;

07.11.95 on PP.1 - 6, 12 and 13.7

 

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