GB2075016A

GB2075016A - Pyridinium Salts

Info

Publication number: GB2075016A
Application number: GB8112786A
Authority: GB
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1980-04-30
Filing date: 1981-04-24
Publication date: 1981-11-11
Also published as: GB2075016B

Abstract

The invention concerns compounds of formula: <IMAGE> wherein the sulphur is bonded to the pyridinium ring at position 2 or 4,Y is -S- or -CH2-, R represents hydrogen, or an alkyl group, or other carboxylic protecting group; R<1> represents hydrogen or lower alkyl; R<2> represents alkyl, aryl or aralkyl; R<3> represents hydrogen or a substituent; q and r are each 1 or 2; and X<(-)> represents a halide ion or an organosulphonate ion, which are antihypertensive agents and are useful as intermediates to captopril and analogous compounds.

Description

SPECIFICATION Pyridinium Salts This invention relates to novel proline derivatives possessing pharmaceutical activity, some of which are useful as chemical intermediates in the preparation of pharmaceutically active proline derivatives.

United States Patent No. 4,105,776 published 8th August, 1978 discloses proline derivatives which are stated to inhibit the conversion of the decapeptide antiotensin I to angiotensin II and are therefore useful in reducing or relieving angiotensin related hypertension. The proline derivatives are disclosed as having general formula (A)

wherein R is hydroxy, NH2 or lower alkoxy; R, and R4 each is hydrogen, lower alkyl, phenyl or phenyllower alkyl;R2 is hydrogen, lower alkyl, phenyl, substituted phenyl wherein the phenyl substituent is haio, lower alkyl or lower alkoxy, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, lower alkylthiomethyl, phenyl-lower alkylthiomethyl, lower alkanoyl-amidomethyl,

R6-S-orR R7; Rs is hydrogen, hydroxy or lower alkyl; R5 is lower alkyl, phenyl or phenyl-lower alkyl; R6 is lower alkyl, phenyl, substituted phenyl, (wherein the phenyl substituent is halo, lower alkyl or lower alkoxy), hydroxy-lower alkyl or amino(carboxy)lower alkyl;

M is O or S; m is 1 to 3; n and p each is O to 2 and processes for preparing.

The asterisks indicate asymmetric carbon atoms.

The preferred isomeric form is stated to be the L-isomer with respect to the carbon of the amino acid, and the D-isomer with respect to the carbon bearing R. For the purposes of the present application such a preferred arrangement of assymetric centres is termed 'D, L configuration'.

A compound failing within the above mentioned formula and described therein, namely 1-(3mercapto-2-D-methylpropanoyl)-L-proline having the generic name captopril, has been extensively investigated and found to be a potent antihypertensive agent (see for example, D. W. Cushman et al., Biochemistry, Vol. 16, 5484 (1977); D. W. Cushman et al, Prog. in Cardiovascular Diseases, Vol. XXI, No. 3, 183 (1 978); Chemistry and Engineering, April 4, (1977); and H. Gavras et al., New Eng. J.

Med., Vol. 298, No. 18, 991(1978)). This compound has the preferred D, L configuration.

U.S. Patent No.4,105,776 also describes a route for the preparation of captopril and related compounds using as intermediates compounds of formula (B)

whereinR,R1, R3, R4, m and n are as defined above and R2 is a group derived from a thioacid of formula R2-SH.

In addition European Patent Publication No. 1978 discloses 3-mercapto-2-methylpropanoyl-4thiazolidine carboxylic acid which has potent antihypertensive activity.

We have now found a class of pyridinium salts which possess pharmaceutical activity and can be used in pharmaceutical compositions. Furthermore, some of these salts can be used as intermediates in a particularly convenient route to captopril and analogous mercapto compounds. These intermediates possess the characteristics of (i) ready convertion to the final products, (ii) easy purification by crystallisation and (iii) facile separation of stereoisomeric forms where mixtures are initially produced.

Accordingly this invention provides compounds of formula:

wherein the sulphur is bonded to the pyridinium ring at position 2 or 4, Y is -S-or -CH2-, R represents hydrogen, or an alkyl group, or other carboxylic protecting group; R1 represents hydrogen or lower alkyl; R2 represents alkyl, aryl or aralkyl; R3 represents hydrogen or a substituent, e.g. alkyl, halogen or alkoxy; q and rare each 1 or 2; and Xo represents a halide ion or an organosulphonate ion, e.g. aryl- or aralkyl- or alkyl-sulphonate ion such as p-toluene-sulphonate- or methanesulphonate.

By the term "lower alkyl" as used herein is meant a branched or straight chain alkyl group having one to seven carbon atoms, such as methyl, ethyl, n-propyl, isopropyl or n-butyl. Lower alkyl groups having up to 4 carbon atoms are preferred and methyl is most preferred.

The term 'halogen' means chlorine, fluorine, bromine or iodine. Xo is preferably a bromide ion.

Examples of alkyl groups for R2 and R3 are lower alkyl groups as described above. Preferably r is 1 and R3 is hydrogen.

The compounds of formula I possess angiotensin converting enzyme (ACE)inhibitory activity and hence are useful as anti-hypertensive agents. The procedure used for detecting ACE inhibitory activity was as follows: Normotensive female rats (300-350 g) were anaesthetised with sodium pentobarbitone (50 mg/kg ip). Blood pressure was monitored from the femoral artery and drugs were administered via a cannula in the femoral vein. The trachea was cannulated to facilitate spontaneous respiration.

Dose response relationships were defined for angiotensin I (Al) and angiotensin II (All) and constant sub-maximal doses were determined to give reproducible pressor responses of about 40 mmHg. In general these doses were in the 0.1-0.2 yg range.

When constant submaximal responses had been obtained to both Al and All, the test compound was administered cumulatively. Ten minutes after each administration of the compound the doses of Al and All were repeated and the dosing cycle continued.

In the above mentioned test procedure a representative compound of formula I, namely N-[2 methyl-3-([1 -methylpyridinium-2-yljthio)propionyl]-L-proline bromide, gave the following results:

Pressor response to Dose Angio ten sin I Angiotensin II Compound (mg/kg) % Predose % Predose 0.01 100 102 Me 0 & 11 110004 104 80 II 1 1 85 77 N CH2CHCON) 10 33 98 Me COOH BrO (A) These results show that the compound (A) possessed substantial ACE inhibitory activity and accordingly is useful as an antihypertensive agent.

Furthermore as mentioned above the compounds of formula I are useful as intermediates to captopril and analogous compounds and provide a convenient means for introducing the mercapto function into the final products. Accordingly this invention also provides a process for preparing a compound of formula

wherein Y, R, R' and r are as defined above which comprises reacting a compound of formula I as hereinbefore defined with an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide, and if desired converting a compound of formula II wherein R is an ester or other carboxy protecting group to a compound of formula II wherein R is hydrogen.

This reaction may be carried out in a suitable solvent such as water or a lower alkanol, e.g.

methanol or ethanol or a mixture thereof. The reaction proceeds at room temperature.

In a preferred embodiment of the aforementioned reaction process the compound of formula I is one wherein R1 is methyl and r is 1, the configuration of the propionyl a-carbon is D and the proline acarbon is L. The product of the reaction using such a starting material is captopril itself when R is hydrogen.

Because the compounds of formula I are salts they are particularly useful as intermediates when it is desired to prepare compounds of formula II having specific stereochemistry. The separation of diastereoisomers from mixtures is generally more easily achieved when diastereoisomers are salts.

Thus the compounds of formula I therefore provide a convenient stage in the synthesis of captopril type compounds at which to isolate the preferred stereochemical isomer having the D, L configuration of asymmetric centres.

This invention also provides a process for preparing a compound of formula I which comprises reacting (a) a pyridothione of '+nrmiiI III nr r'r

wherein R2, R3 and q are as hereinbefore defined, with a compound of formula

wherein hal is halogen; Y, R, R1 and r are as hereinbefore defined, or (B) a compound of formula II

wherein Y, r, R and R' are as hereinbefore defined with a compound of formula

wherein XO, R2, R3 and q are as hereinbefore defined, and the fluorine is in position 2 or 4, or (C) a compound of formula VII

wherein the sulphur is bonded to position 2 or 4 of the pyridine ring, and r, q, R, R1, Y and R3 are as hereinbefore defined, with an alkylating, arylating or aralkylating agent containing the groups R2 and X, e.g. a lower alkyl- or aralkyl- halide or a lower alkyl-, aryl- or aralkyl-sulphonic acid lower alkyl or aralkyl ester.

A compound I in which xe is one particular anion may be converted to another in which Xo is a different anion by anion exchange, e.g. chloride may be exchanged for iodide by reaction of a chloride of formula I with sodium iodide in ethanol or other suitable solvent.

After any of the aforementioned reactions individual diastereoisomers of formula I may be isolated by conventional means, e.g. fractional crystallisation, high performance liquid chromatography.

The invention includes a method of treating hypertension in a mammal which method comprises administering to said mammal an effective amount of an antihypertensive agent of formula I as defined above. The amount used will depend on the needs of the mammal being treated and the activity of the compound used but may vary from 1 to 100 mg/kg.

The invention also provides a pharmaceutical composition comprising a compound of general formula (I) in association with a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical composition. In such a composition, the carrier is generally a solid or liquid, or a mixture of a solid and a liquid.

Solid form compositions include powders, granules, tablets, capsules (e.g. hard and soft gelatin capsules), suppositories and pessaries. A solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99%, e.g. from 0.03 to 99%, preferably 1 to 80% of the active ingredient.Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similariy cachets are included.

Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and pressurised compositions. The active ingredient, for example, can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweetners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers or osmo-regulators.

Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycerol and glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilised by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. When the compound is orally active it can be administered orally either in liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

The quantity of the active ingredient in a unit dose of composition may be varied or adjusted from 0.5 mg. or less to 750 mg. or more, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of the carrier where the compounds are in unit dosage form.

The following Examples illustrate the invention: Example 1 N-[2-Methyl-3-(1 -methylpyridiniu m-2-yl]thio)propionyl]-L-proline Bromide (a) A solution of N-(3-bromo-2-methylpropionyl)-L-proline (1.0 g) and 1 -methyl-2-pyridothione (0.5 g) in acetonitrile (25 ml) was heated at reflux for 5 hours. The solvent was removed by evaporation and the residue was triturated with ether and then with acetone to give a solid. This solid was removed by filtration and dried to give the title compound, hemihydrate (0.2 g), m.p.1 70-50C.

Analysis Found: C,45.1; H, 5.3; N, 6.7 C,5H2,BrN203S .-H20 requires: C, 45.2; H, 5.6; N, 7.0%.

(b) A solution of the product of step (a) above in a mixture of 10% methanol and 90% acetonitrile was fractionally crystallised to give N-[2-D-methyl-3-[1 -methylpyridinium-2-yl]thio)propionyl]-L- proline bromide.

Example 2 1 -(3-Mercapto-2-D-methylpropionyl)-L-proline N-[2-D-Methyl-3([1 -methylpyridiniu m-2-yl]thio)-propionyl]-L-proline bromide (3.98 g) prepared according to Example 1 (b) was dissolved in methanol (40 ml) and the solution was treated with a solution of sodium hydroxide (0.4 g) in methanol (40 ml). The solvent was removed by evaporation and the residue was dissolved in chloroform and filtered to remove sodium bromide. The residue was evaporated and triturated with ethyl acetate to give the title compound.

Example 3 N-[2-Methyl-3-( [1 -benzylpyridinium-2-yl]thio)propionyll-L-proline Bromide Using a procedure analogous to Example 1, N-(3-bromo-2-methylpropionyl)-L-proline and 1benzyl-2-pyridothione are reacted to give the title comppund.

Example 4 N-[2-methyl-3-([1 -phenylpyridinium-2-yljthio)propionylj-L-proline Bromide Using a procedure analogous to Example 1 N-(3-bromo-2-methylpropionyl)-L-proline and 1phenyl-2-pyridothione are reacted to give the title compound.

Example 5 N-[2-Methyl-3-(1,6-dimethylpyridinium-2-yl]thio)propionyl]-L-proline Bromide Using a procedure analogous to Example 1 N-(3-bromo-2-methylpropionyl)-L-proline and 1,6dimethyl-pyridothione are reacted to give the title compound.

Example 6 3-[2-Methyl-3-( [1 -methylpyridiniu m-2-yl]thio)propionyl]-4-thiazolidinecarboxylic Acid, Bromide Using a procedure analogous to Example 1 3-(3-bromo-2-methylpropionyl)-4thiazolidinecarboxylic acid is reacted with 1 -methyl-2-pyridothione to give the title compound.

Example 7 N-[2-Methyl-3-( [1 methylpyridiniu m-2-yl]thio) propionyl]-L-proline Tosylate Using a procedure analogous to Example 1 N-(3-tosyloxy-2-methylpropionyl)-L-proline and 1methyl-2-pyridothione are reacted to give the title compound.

Claims

1. A compound of formula:

wherein the sulphur is bonded to the pyridinium ring at position 2 or 4, Y is-S-or -CH2-, R represents hydrogen, or an alkyl group, or other carboxylic protecting group; R1 represents hydrogen or lower alkyl; R2 represents alkyl, aryl or aralkyl; R3 represents hydrogen or a substituent; q and r are each 1 or 2; and Xs represents a halide ion or an organosulphonate ion.

2. A compound of formula I as claimed in Claim 1 wherein R2 represents lower alkyl, and R3 and R represent hydrogen.

3. A compound of formula I as claimed in Claim 1 or Claim 2 wherein Xis a bromide ion.

4. A compound of formula I as claimed in any one of Claims 1 to 3 wherein the sulphur is bonded to the pyridinium ring at position 2.

5. N-[2-Methyl-3-([1 -methylpyridinium-2-yI]-thio)propionyl]-L-proline bromide.

6. A process for preparing a compound of formula I as defined in Claim 1 which comprises (A) reacting a pyridothione of formula Ill or IV

wherein R2, R3 and q are as defined in Claim 1, with a compound of formula (V)

wherein hal is halogen; Y, R, R1 and rare as defined in claim 1, to give a compound of formula I wherein Xe is a halide ion, or (B) reacting a compound of formula II

wherein Y, r, R and R' are as hereinbefore defined with a compound of formula

wherein Xe, R2, R3 and q are as defined in Claim 1, and the fluorine is in position 2 or 4, or (C) reacting a compound of formula VII

wherein the sulphur is bonded to position 2 or 4 of the pyridine ring, and r, q, R, R', Y and R3 are as defined in Claim 1 , with an alkylating, arylating or aralkylating agent containing the groups R2 and X.

7. A process (A) as claimed in Claim 6 wherein hal is bromine.

8. A process (C) as claimed in Claim 6 wherein the alkylating, arylating or aralkylating agent is a lower alkyl- or aralkyl-halide.

9. A process for preparing a compound of formula I as defined in Claim 1 substantially as hereinbefore described with reference to any one of Examples 1 (a) and 3 to 7.

10. A compound of formula I whenever prepared by a process as claimed in any one of Claims 6 to 9.

11. A compound of formula I as defined in any one of Claims 1 to 5 for use as an antihypertensive agent.

12. A pharmaceutical composition comprising a compound of formula I as claimed in Claim 1 and a pharmaceutically acceptable carrier.

13. A process for preparing a compound of formula

wherein Y, R, R' and r have the meanings defined in Claim 1 which comprises reacting a compound of formula I as defined in Claim 1 with an alkali metal hydroxide, and if desired converting a compound of formula II wherein R is alkyl or other carboxy protecting group to a compound of formula II wherein R is hydrogen.

14. A process as claimed in Claim 13 wherein Y is -CH2-; R' is methyl; r is 1, and the configuration of the propionyl a carbon atom is D and the proline a-carbon is L.

15. A process for preparing a compound of formula II as claimed in Claim 13 substantially as hereinbefore described with reference to Example 2.