DK172007B1 - Pharmaceutically active derivatives of (R)-5-pentylamino- 5-oxopentanoic acid, and pharmaceutical preparations thereof - Google Patents

Description

in DK 172007 B1

The present invention relates to novel derivatives of (R) -5-pentylamino-5-oxopentanoic acid which may be reproduced by the general formula

COOH

(CH2) 2 (*) CH-NH-CO-R-1 (CH2) 4-CH3 (I)

CO-N

Wherein R 1 is selected from the group consisting of 2-naphthyl, 3,4-dichlorophenyl and 3,4-dimethylphenyl, and R 2 represents a pentyl group or an alkoxyalkyl group having 4 carbon atoms and the substituents thereof chiral central group (marked with a star in formula (I)) has R configuration (rectus), and pharmaceutically acceptable salts thereof, with the proviso that when R 1 is 3,4-dichlorophenyl or 3.4 -dimethyl-phenyl, R 2 is not a pentyl group.

R2 is preferably selected from pentyl, 2-ethoxyethyl and 3-methoxypropyl groups.

GB-A-2 160 869 and European Journal of Medicinal 30 Chemistry, Vol. 21, No. 1, pages 9-20 (1986) describe racemic compounds of formula I wherein R 1 is 3,4-dimethyl- phenyl or 3,4-dichlorophenyl and R 2 is pentyl.

The present compounds exhibit potent antagonistic activity against cholecystokinin (CCK). Therefore, the compounds of the present invention may advantageously be used in the treatment of various diseases in humans, such as diseases of the digestive system, e.g. in the treatment of colitis, biliary dyskinesia and pancreatitis.

On the basis of their pharmacological properties, 40 can also be considered for their use in the treatment of mental disorders, which may be attributed to deficiencies in the physiological neuronal levels of CCK or of other related bioactive polypeptides, and in the treatment of anorexia.

The compounds of this invention have, as mentioned, a strong anti-CCK activity in various experimental situations, both in vivo and in vitro.

Thus, at nanomolar concentrations, they inhibit the binding of labeled cholecystokinin to the gallbladder cell membranes of an ox, a tissue believed to be a target organ for the physiological action of cholecystokinin.

In addition, these compounds are also very active in vivo. Eg. they inhibit, in a dose-dependent manner, some even at a dose of less than 0.1 mg / kg, the contraction and depletion of the gallbladder induced by egg yolk, which induces the endogenous release of CCK. They also encourage the emptying of the stomach by inhibiting the pyloric contraction caused by CCK.

In addition, their protective effect is particularly strong against experimental pancreatitis, e.g. against pancreatitis induced by sodium taurocholate.

The invention further relates to a pharmaceutical composition characterized in that it comprises one of the compounds according to claim 1 or a pharmaceutically acceptable salt thereof as the active ingredient.

Pharmaceutical forms of the compounds encompassed by the invention can be prepared by conventional techniques, e.g. such as pills, capsules, suspensions, solutions and suppositories, and may be administered orally, parenterally or rectally.

Typically, the active ingredient is administered to patient 30 in an amount of from 0.005 to 5 mg / kg body weight per day. dosage.

For parenteral administration, it is preferred to use a water-soluble salt of the subject compounds, such as the sodium salt or other salt, which is nontoxic and pharmaceutically acceptable. Substances commonly used in the pharmaceutical industry, such as excipients, binders, flavors, dispersants, dyes and humectants, may be used as inactive ingredients.

The present invention is based on the following two findings: A) Anti-cholecystokinin activity of the compounds disclosed in the above patent literature is due to the enantiomeric R forms corresponding to the starting D-glutamic acid. This fact is quite surprising considering the fact that the naturally occurring amino acids which are biologically active all belong to the L series.

(B) The method of preparation described in the aforementioned patent literature does not allow the configuration to be maintained, i.e. whether L-glutamic acid or D-glutamic acid is used as starting material, pentanoic acid derivatives (R, S) are obtained.

For the preparation of the compounds of the present invention, there is provided a process which ensures that the configuration is maintained at successive 20 conversions and therefore enables the 5-pentylamino-5-oxopentanoic acid derivatives to be obtained from D-glutamic acid in the optical active R-form (rectus form), which is the pharmacologically active, enantiomeric form.

The process of preparing the compounds 25 of the present invention comprises the steps of: a) reacting the in-benzyl ester of N-carbobenzoxy-D-glutamic acid with an amine of formula (CH 2) 4-CH 3

H-N

Where R 2 is as defined above, by the mixed anhydride method in an inert anhydrous solvent at a temperature between -15 ° C and + 15 ° C to give the compounds of formula (III) (see reaction scheme below B) debenzylation and decarbobenzoxylation of the compound of formula (III) dissolved in an inert solvent by reacting with hydrogen at room temperature and atmospheric pressure in the presence of a catalytically effective amount of a hydrogenation catalyst to obtain the derivatives c) reacting the derivatives of formula (II) under Schotten - Bauman conditions with an equivalent amount of an acyl chloride of formula R , at a temperature of from 0 ° C to 15 ° C and recovery of (R) -4-acylamino-5-pentylamino-5-oxopentanoic acid derivatives of formula (I) from the reaction mass.

The sequence of steps in this procedure is illustrated as a whole in the reaction scheme below: 15 COOH2 - C6H5 cooh2 - C6H5 (ch2) 2 (ch2) 2 Amidation -> ch-nh-co-o-ch2 -c6h5 (ch2) ch3 ch-nh-co-o-ch2-c6h5 HN (CH2) 4-CH3 COOH \ /

Ro CO-N

\ (step a) Ro (III) 30

Hydrogenation COOH Acylation COOH

-> -> (Step b) (CH 2) 2 R 2 CO-Cl (CH 2) 2 (Step c) CH-NH 2 CH-NH-CO-R! (CH 2) 4-CH 3 (CH 2) 4-CH 3

CO-N CO-N

2 (ID (I)

The amidation step (a) is preferably carried out at a temperature between -15 ° C and -10 ° C for a period of 1-24 hours, preferably for 6 hours, with the reagents in a stoichiometric ratio. The preferred solvent for the reaction is selected from chloroform, dioxane and tetrahydrofuran.

The hydrogenation step (b) is preferably carried out in the presence of palladium supported on carbon with between 0.02 and 0.001 atoms of palladium per minute. mole of the compound (III) in a methanolic solution at room temperature and normal pressure in a hydrogen stream for a period of from 1-12 hours, preferably 10 3 hours.

The acylation step (c) is preferably carried out at a temperature of approx. 5 ° C for a period of from 1-24 hours, preferably 12 hours.

The following examples are included for better illustration of the invention.

Example 1

Preparation of the benzyl ester of (R) -4-carbobenzoxylamino-5- (di-n-pentylamino) -5-oxopentanoic acid (Compound 1 in Table 20

Dissolve 37.1 g (0.1 mole) of the in-benzyl ester of N-carbobenzoxy - D-glutamic acid in 250 ml of anhydrous tetrahydrofuran, cool the solution to -10 ° C and 10.1 g (0.1 mole) of triethyl -amine is added with stirring. Then 10.8 g (0.1 mole) of ethyl chlorocarbonate are added, still at -10 ° C. The temperature is maintained at -10 ° C for 20 minutes, after which 15.7 g (0.1 mole) dipentylamine is added. Stirring is continued for a further 6 hours and the temperature rises to room temperature. The solution is dried and the residue is taken up in ethyl acetate.

It is washed with 2N HCl, sodium bicarbonate and finally with water, then dried over anhydrous Na 2 SO 4. Concentrating to a small volume gives an oily residue (etc. 510.6) which does not crystallize, with a chromatographic purity of more than 95%.

TLC: Rf 0.81 (chloroformethyl acetate 7/3 v / v).

46.5 g are obtained, yield 91%.

6 DK 172007 B1

All compounds of formula III are synthesized by the same method (see above scheme). The compounds obtained, together with some identifying characteristics as well as the yields obtained, are shown in Table I.

5

TABLE I

Derivatives of the formula: cooch2 - c6h5 10 ch2 CH2 CH-nh-cooch2 - c6h5 20 C (CHoU-CHo // \ /

0 N

\ 25 R2

Compound R2 Rf1 Formula 30 1 pentyl 0.71 C30H42N2 ° 5 2 3-methoxypropyl 0.22 C29H40N2 ° 6 3 2-ethoxyethyl 0.28 C29H40N2

Eluent: chloroform / ethyl acetate 9/1 vol./vol.

35

Example 2

Preparation of (R) -4-amino-5- (di-n-pentylamino) -5-oxopenic acid (Compound 4 of Table II).

51.1 g (0.1 mol) of the benzyl ester of (R) -4-carbobenz-40-zoxyamino-5- (di-n-pentylamino) -5-oxopentanoic acid are dissolved in 300 ml of methanol with the addition of 1 g of 10% s palladium on carbon and hydrogenated at room temperature with a hydrogen stream for 3 hours. The catalyst is filtered off and the methanol is distilled off under vacuum. An oily residue (etc. 286.4) which does not crystallize is obtained with a chromatographic purity greater than 95%.

TLC: Rf 0.75 (n-butanol / acetic acid / H 2 O 5/2/2 v / v).

All compounds of formula II are synthesized by the same method (see above scheme). The compounds obtained, together with some identifying characteristics as well as the yields obtained, are shown in Table II below.

10

TABLE II

Derivatives of the formula:

COOH

CH 2 CH 2 CH-NH 2 25 C (CH 2) 4-CH 3 //

0 N

\ 30 R2

Compound R2 Rf1 Formula 35 4 pentyl 0.73 ^ 15 ^ 30 ^ 2 ^ 3 5 3-methoxypropyl 0.58 ^ 14H28N2 ^ 4 6 2-ethoxyethyl 0.62 C14H28N2 ° 4

Eluant: n-butanol acetic acid / H2 O: 5/2/2 40 vol./vol./vol.

8 DK 172007 B1

Example 3

Preparation of (R) -4- (2-naphthylamino) -5- (di-n-pentylamino) -5-oxopentanoic acid (Compound 7 of Table III).

28.6 g (0.1 mole) of (R) -4-amino-5- (di-n-pentylamino) -5-5-oxopentanoic acid are suspended in 300 ml of water and then dissolved with stirring by adding 10.1 g (0.1 mole) sodium carbonate. Then, 19.1 g (0.1 mole) of 2-naphthoyl chloride are added over 1 hour at 0 ° C with stirring.

The mixture is left for 12 hours for reaction.

It is acidified on congruent with dilute HCl and the resulting precipitate is filtered off. It crystallizes from H 2 O / ethanol (2/1). Mp. 69-72 ° C.

TLC: (iso-amyl alcohol / acetone / H2 O 5/2/1): Rf 0.83.

37 g (m.p. 440.6) are obtained, yield 84%.

Specific rotation: [α] p = + 11.0 ° (c = 2.5% in 95% ethanol).

All compounds of formula I are synthesized by the same method (see above scheme). The compounds obtained, together with some identifying characteristics as well as the yields obtained, are shown in Table III below.

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For comparison of the anti-CCK activity of the derivatives of (R) -5-pentylamino-5-oxopentanoic acid with the corresponding enantiomers of the (S) series, some of these derivatives have been synthesized by the method described above, but in that in this case, starting from the i-benzyl ester of N-carbo-benzoxy-L-glutamic acid.

Table IV lists some of the (S) -4-acylamino-5- (di-n-pentylamino) -5-oxopentanoic acid derivatives obtained in this way and used for the pharmacological comparisons, together with some of their identifying characteristics. .

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The potent anti-cholecystokinin activity of the compounds of the invention is now to be documented by a series of pharmacological tests conducted both in vitro and in vivo.

5

Studies on the binding to cell membranes of oxaldehyde.

The capacity of some of the compounds of the invention and of some of the corresponding enantiomers of the (S) series to inhibit the binding of [125-1] -Bolton-10 comparison with the displacement caused by cold (unlabelled) CCK.

The oxen bladder cell membranes are homogenized with Tris buffer (pH 7.4) and the homogenate centrifuged at 50,000 g for 10 minutes. Subsequently, the membranes are incubated with a radioactive tracer and the tested compounds for 2 hours at 25 ° C.

After the above liquid has been discarded, the radioactivity associated with the bead is determined with a liquid scintillator. The specific binding is determined as the difference between the binding in the absence and in the presence of 10 "6M CCK-8.

The results obtained are shown in Table V, which shows IC-50, i.e. the concentration (in moles / liter) of the antagonist capable of displacing 50% of [125-1] - CCK-8 from the receptors.

13 DK 172007 B1

TABLE V

Inhibition of the binding of (125-1) - (BH) -CCK-8 (R) -For-IC-50 (S) -For-IC-50 5 binder (mol / liter) binder (mol / liter) CCK- 8 0.2 x 10 "9 Example 13 6.1 x 10" 8

Conn. 7 1.0 x 10 "9" 16 5.6 x 10 "7" 10 6.2 x 10 "9 10" 11 3.0 x 10 "8" 12 9.3 x 10 “9

From the data given in Table V, it can be seen that the 15 compounds here antagonize 50% of the binding of CCK at a concentration which for the most active (R) compound is only 5 times greater than the activity of the specific antagonist, thus exhibiting a very high specificity of action. The corresponding (S) enantiomers are on average 50-90 times less active.

To confirm what was shown in this in vitro study, some of the compounds have also been tested in vivo.

25 Antisoastic activity of the gallbladder in mice.

The emptying of the gallbladder is induced by a single oral administration of 1 ml of a 30% (w / v) suspension of lyophilized egg yolk in a physiological solution.

Once absorbed, the egg yolk, as indicated above, induces the release of endogenous CCK. This dose has been selected as it causes virtually complete emptying of the gallbladder.

The antagonist compounds are administered intraperitoneally (i.p.) 15 minutes before the contraceptive.

The percent antispastic activity for each dose has been calculated using the following formula: 14 DK 172007 B1

Pi - P2% = pT1 x x 100 where PL is the average weight of gallbladder in the group of animals treated with drug plus contraceptive, P2 is the average weight of gallbladder in the group of animals treated only with contraceptive, and 10 P3 is the average weight of the gallbladder in the control group of animals.

The compounds have been tested at various doses to enable the ID-50 value to be calculated, i.e. the dose (in mg / kg i.p.) capable of inhibiting the contracting effect of the egg yolk by 50%.

The results thus obtained are shown in Table VI, where the effects obtained are expressed as ID 50.

15 DK 172007 B1

TABLE VI

Antispastic activity on gallbladder contraction induced by egg yolk.

Compound Dosage% Inhibition of Empty ID50 (1) (mg / kg gallbladder (mg / kg ip.) Ip) 7 (R) 0.025 24.0 0.05 10 0.05 44.2 0.1 74 0 (0.99) 13 (S) 1 18.8 3.2 3 47.7 15 9 80.2 (0.99) ATROPINE 5 3.7

21.6 INACTIVE

15 10.5 20 - PAPAVERIN 25 0

50 0 INACTIVE

75 26.1 25 (1) r = Correlation coefficient for the right regression line.

The emptying of the gallbladder is diminished in a dose-dependent manner by the compounds of the present invention. Compound 7 blocks at a dose of 0.1 mg / kg the contraction induced by the yolk with approx. 75%. Its (S) enantiomer is also active, but with an ID-50 value of approx. 60 times larger. On the other hand, atropine is inactive and papeverin is slightly active, but only at the toxic dose of 75 mg / kg, which causes 20% of the treated animals to die.

16 DK 172007 B1

Antispastic activity on piloric contraction in rats.

This experiment demonstrates the contracting effect of CCK on the pyloric ring muscle. A dose of 8 i.p. CCK, which produces a sub-maximal contraction of the pilorus.

The antagonistic compounds are administered (i.p.) 15 minutes before the contraceptive. Ten minutes after administration of the contraceptive, the animals are treated per day. us with 25 ml / kg H2O. Five minutes after this administration, the animals are killed, their stomachs removed and the stomach contents measured by removal with a spray of tea.

The percent antispastic activity for each dose administered is calculated from the following formula: 15 v2 "vl% = 77-77- x 100 v2" v3 where 20V] is the volume of the stomach contents of the group of animals treated with the drug plus the contraceptive, V2 is the volume of the stomach contents of the group of animals treated only with the contraceptive, and V3 is the volume of the stomach contents of the control group of animals.

The compounds are tested at different doses so that it is possible to calculate the ID-50 value, ie. the dose (in mg / kg i.p.) capable of inhibiting the contracting effect of CCK by 50%.

The results obtained are shown in Table VII, where the 30 effects obtained are expressed as ID-50.

17 DK 172007 B1

TABLE VII

Antispastic activity on piloric contraction induced by CCK in rats.

Compound Doses% inhibition of ID50 (1) (mg / kg piloric contract (mg / kg ip) tion ip) 7 (R) 0.01 27.7 10 0.03 48.8 0.03 0.1 80 , 8 (0.99) 13 (S) 1 17.7 4.55 3 39.0 15 5 54.2 (0.99) (1): in parentheses r = the correlation coefficient of the right regression line.

The pyloric contraction caused by 8 μg / kg CCK-8 is inhibited by 50% of some of the compounds of the invention at very low doses, 30 Mg / kg for compound 7, ie. at a dose only 3-4 times greater than that of the hormonal contraceptive. On the other hand, Compound 13, which is the (S) enantiomer of Compound 7, is only active at doses which are approx. 150 times higher.

Pancreatitis induced by sodium taurocholate.

The method described by Aho et al. (Scan-30 dinavian J. Gastroenterology 15 (1980), 411-16), followed.

Male rats weighing approx. 250 g, are subjected to lapara-tomi, and the pancreas is exposed. 0.3 ml of a 6% sodium taurocholate solution is injected directly into the pancreatic tissue.

The products under test are administered intraperitoneally (i.p.) 30 minutes before surgery and 3 hours after surgery. Six hours after the laparotomy and after anaesthesia with blood, blood is removed from the retroorbital plexus, the animals are killed, and the pancreas is removed and weighed. The activity of the serum amylase is determined by the Ceska method (Clin. Chim. Acta.

26 (1969), 437-444).

The compounds are tested at different doses so that it is possible to calculate the ID-50 value, ie. the dose (in mg / kg ip) capable of inhibiting the toxic effect of the sodium taurocholate by 50%, expressed both as a percentage inhibition of the weight gain of pancreas and as a percentage inhibition of the increase in serum amylase . The results obtained with compound 7 are shown in Table VIII.

DK 172007 Pg 19

TABLE VIII

Examples of proteolytic activity of the subject compounds in experimental pancreatitis caused by taurocholate in rats.

5 Percent% Inhibit Amylase% Inhibition of Pancreatic Weight Serum Increase Weight to Increase (U / ml) in Amylase Animal Weight (ID50 mg / kg ip) (ID50 mg / kg ip) 10 Control 0.40 - 8 , 3

Check +

Taurocholate 0.51 - 14.7 ---

Compound 7 (0.3 mg / kg) +

Taurocholate 0.47 36.4 12.0 42.2 20

Compound 7 (1 mg / kg) +

Taurocholate 0.45 54.5 9.6 79.7 25

Compound 7 (3 mg / kg) +

Taurocholate 0.41 90.8 9.0 89.0 ID 50 = 0.6 (r = 0.98) ID 50 = 0.4 (r = 0.94)

Check 0.37 - 7.9

Check 35+

Taurocholate 0.54 - 16.0 (r) = Correlation coefficient 40

Sodium taurocholate induces pancreatitis which causes a weight gain of the organ which also becomes edema, lacks elasticity and is hemorrhagic.

Moreover, the serum amylase nearly doubles. These effects are blocked in a dose-dependent manner by the compounds of this invention. Eg. inhibits a dose of approx. 0.5 mg / kg i.p. of compound 7 the increase in weight of the pancreas and the increase in serum amylase by 50%.

20 DK 172007 B1

Thus, the experimental data shown above have shown the possible utility of these compounds in the treatment of various pathological conditions affecting the digestive tract, e.g. in spastic syndromes and pain in general, such as biliary diskinesia, or to stimulate the emptying of the stomach, thereby stimulating digestion.

These products can be used with particular benefit in the treatment of pancreatitis, as surely active drugs whose efficacy has been shown by sustained pharmacological tests are lacking for this pathological condition. A favorable therapeutic application may also be met for many of the compounds of this invention in the treatment of various forms of anorexia, and also in the treatment of certain pathological conditions in the CNS, which are associated with 15 deficiencies in the physiological neuronal levels of CCK or other bioactive peptides.

Claims (7)

1. Pharmaceutically active derivatives of (R) -5-pentylamino-5-oxopentanoic acid # characterized in that they have the general formula 5 COOH (CH 2) 20 (*) CH-NH-CO-R 1 Wherein (R 2) is selected from 2-naphthyl, 3,4-dichlorophenyl and 3,4-dimethylphenyl, and R 2 represents a pentyl group or an alkoxyalkyl group having 4 carbon atoms, and wherein the substituents on the chiral central group (marked with a star in formula (I)) have R configuration (rectus) and pharmaceutically acceptable salts thereof, with the proviso that when R 1 is 3,4-dichlorophenyl or 3,4 -dimethylphenyl, R 2 is not a pentyl group. Derivative according to claim 1, characterized in that R 2 is selected from the group consisting of pentyl, 2-ethoxyethyl and 3-methoxypropyl groups. Pharmaceutical composition, characterized in that it comprises one of the compounds of claim 1 or a pharmaceutically acceptable salt thereof as the active ingredient. Pharmaceutical composition according to claim 3, characterized in that it is for use in therapy on the basis of its antispastic activity. Pharmaceutical composition according to claim 3, characterized in that it is for use in the treatment 40 of pancreatitis. DK 172007 B1 Pharmaceutical composition according to claim 3, characterized in that it is for the treatment of pathological conditions in the CNS that are linked to deficiencies in the physiological neuronal levels of cholecystokinin or other related bioactive polypeptides. Pharmaceutical composition according to claim 2, characterized in that it further comprises inactive, pharmaceutically acceptable ingredients selected from excipients, binders, flavoring agents, dispersing agents, preservatives, wetting agents and mixtures thereof.