GB2165243A - 17-sulphonamido yohimbane derivatives - Google Patents

Abstract

The invention concerns hypotensive and antihypertensive compounds having the formula <IMAGE> or salts thereof wherein R represents hydrogen or lower alkyl, R<1> represents lower alkyl, halolower alkyl, aryl, heteroaryl, or a group of formula R<2>R<3>N-A- wherein R<2> and R<3> independently represent hydrogen, lower alkyl, aryl or aryl lower alkyl or R<2> and R<3> together with the nitrogen atom to which they are attached represent a ring selected from pyrrolidino, piperidino or morpholino; A represents a direct bond between the S and N atoms or a lower alkylene group having 1 to 3 carbon atoms between the S and N atoms, and R<4> and R<5> independently represent hydrogen or a substituent selected from halogen, lower alkyl and lower alkoxy.

Description

SPECIFICATION Yohimbane derivatives This invention relates to heterocyclic compounds more particularly to yohimbane derivatives, processes for their preparation and pharmaceutical compositions comprising them.

The present invention provides compounds of formula:

and salts thereof wherein R represents hydrogen or lower alkyl, R' represents lower alkyl, halolower alkyl, aryl, heteroaryl, or a group of formula R2R3N-A- wherein R2 and R3 independently represent hydrogen, lower alkyl, aryl or aryllower alkyl or R2 and R3 together with the nitrogen atom to which they are attached represent a ring selected from pyrrolidino, piperidino or morpholino; A represents a direct bond between the S and N atoms or a lower alkylene group having 1 to 3 carbon atoms between the S and N atoms, and R4 and R5 independently represent hydrogen or a substituent selected from halogen, lower alkyl and lower alkoxy.

The term "lower" as used herein to qualify alkyl or alkylene means that such a radical contains 1 to 6 carbon atoms, preferably 1 to 4. Lower when used to qualify alkenyl means 2 to 6 carbon atoms.

Examples of lower alkyl groups for any one of R, RI, R2, R3, R4 and R5 are methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl and n-hexyl. Examples of lower alkoxy for R4 and R5 are methoxy, ethoxy, npropoxy and n-butoxy.

The term aryl includes radicals such as phenyl, naphthyl and phenyl substituted for example by one or more groups selected from lower alkyl, (e.g. methyl, ethyl, n-propyl), halogen (e.g. chlorine or bromine) and lower alkoxy (e.g. methoxy, ethoxy, n-propoxy). The term "heteroaryl" means a monovalent aromatic heterocyclic group in which the ring heteroatom or atoms is/are selected from 0, N and S. Examples of heteroaryl radicals are pyridyl, thienyl, furyl and thiazolyl.

When A is a lower alkylene group the group may be a branched or straight chain provided that there are 1 to 3 carbon atoms in the chain between the N and S atoms. For example the lower alkylene group may be methylene, ethylene, trimethylene or a branched group such as ethylethylene or propylene [7CH(CH3).CH2-j.

The compounds of formula I possess pharmaceutical activity in particular hypotensive and antihypertensive activity and accordingly are indicated for use in the treatment of elevated blood pressure. Compounds of formula I were tested for their ability to lower blood pressure by one or both of the following standard procedures: Procedure A Female Charles River rats (50-70 g) are rendered hypertensive by subcutaneous implantation of deoxycorticosterone acetate (DOCA) pellets (30 mg) and unilateral nephrectomy under halothane anesthesia.

The drinking water is replaced with 0.9%, w/v, saline for the subsequent 4 weeks. After an additional 2 weeks, systolic blood pressures are measured in a 37"C constant-temperature housing by a tail-cuff technique. Tail pulses were detected by a pneumatic pulse transducer (Narco Biosystems) and recorded on a Devices MX2 recorder. Rats with systolic pressures below 155 mmHg are discarded.

Groups of four hypertensive rats are dosed orally with the test substance in 0.5% (hydroxypropyl) methylcellulose/0.9% saline vehicle (l0mLlkg) or vehicle alone. Blood pressures are recorded before dosing and at selected time points afterwards. Results are appraised statistically by an analysis of variance.

Procedure B The blood pressures of male or female spontaneously hypertensive rats are measured in a 37C constant temperature housing by means of a tail cuff. Rats with systolic pressures below 155 mmHg are discarded. Groups of rats are dosed orally with the test substance in a suitable vehicle or with alone. Systolic pressures are recorded before dosing and at selected time points afterwards. Heart rates are derived from caudal artery pulses. Results are analysed statistically by means of 2 way analysis of variance (within group).

The results of the antihypertensive testing of representative compounds of the invention by the procedures A and B are given in the following Table: Dose Blood Pressure as % Compound Procedure mMollKg of pre-dose level ftime t p.o. after dosing) t=2 hours 6 hours 24 hours N-(Yohimban-17ss-yl) A 0.130 39.8 54.1 63.4 methane-sulphon amide A 0.015 68.3 103.5 117.2 N-Methyl-N- A 0.150 43.9 60.8 79.1 (yohimban-1 7i3-yl) methane- A 0.075 46.9 39.3 63.8 sulphonamide A 0.030 48.9 49.6 95.6 B 0.003 79.1 83.8 99.3 These results show the compounds of formula I to be potent antihypertensive agents.

The compounds of formula I may be prepared by reacting an amine of general formula:

with a reactive derivative of a sulphonic acid of general formula: RiSO2OH (Ill) in which formulae R, Ri, R4 and R5 are as defined hereinabove. As examples of reactive derivative of the acid of general formula (III) mention is made of the halide and the anhydride. Most preferably the reactive derivative is the chloride. The reaction is conveniently carried out under basic conditions, for example in the presence of a tertiary amine, e.g. triethylamine. The reactive derivatives of the sulphonic acid are known compounds or can be prepared by known methods.The amines of formula Il are also known compounds or can be prepared in known manner from 17-yohimbanone or derivatives thereof, for example by the following schemes A and B Scheme A

Scheme B

R6= alkyl In order to obtain the desired 17p-amino compound the intermediate amines or imines should be reduced with a sterically undemanding reducing agent. For example reduction with sodium in ethanol in Scheme A produces the desired 17P-amino compound. In Scheme B reduction using sodium borohydride also produces the desired 17ss-alkylamino compound.

A further process for preparing the compounds of formula I wherein R is lower alkyl comprises aikylating a compound of formula I wherein R is hydrogen. The alkylation is conveniently carried out using a di(lower-alkyl) sulphate preferably in the presence of a phase transfer catalyst, e.g. nBu4NHSO4.

An alternative method of preparing the compounds of the invention where R' is R2R3N-A- involves reaction of a compound of formula (IV)

(where R, R4, R5 and A are as defined above and X is halogen, preferably chlorine) with ammonia or an amine of formula (V)

where R2 and R3 are as defined above. The starting materials of formula (lV) in which A is lower alkylene may be prepared by, for example, reacting a reactive derivative of a o-haloalkanesulphonic acid with a compound of formula (II). The aminosulphonyl halide starting materials of formula (lV) in which A is a direct bond may be prepared by halogenating the corresponding aminosulphonic acid.

A further method for preparing the compounds of the invention in which RI is R2 R3 N-A- wherein A is a direct bond comprises reaction of a compound of formula (11) with a sulphonamide derivative of the formula

(where R2 and R3 have the meanings given above). Preferably the compound VI is sulphamide i.e. the compound in which both R2 and R3 are hydrogen.

A preferred method for preparing certain compounds of the invention in which R is R2 R3 N-A- wherein A is a lower alkylene group of at least two carbon atoms comprises adding ammonia or an amine of formula (V) to a compound of formula (VII)

where R, R4 and R5 have the meanings given above and R7 is a lower alkenyl group. A preferred lower alkenyl group is vinyl.The compounds of formula (VII) may be prepared by condensing a reactive derivative of an alkenesulphonic acid (e.g. the sulphonyl chloride) with an amine of the formula (II). Alternatively the amine of formula (II) may be reacted with an appropriate o-haloalkane sulphonyl chloride, particularly a ss-haloethanesulphonyl chloride, under conditions basic enough to eliminate hydrogen chloride from the condensation product.

Compounds of the invention in which R2 and/or R3 are lower alkyl or aryl(lower)alkyl, in particular those compounds in which A is a lower alkylene group, may be prepared by alkylating or arylalkylating corresponding compounds in which R2 and/or R3 is hydrogen. The alkylation or arylalkylation may be carried out with, for example, a (lower)alkylhalide or aryl(lower)alkylhaiide under basic conditions.

If in the processes described above the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compound.

Examples of acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic and p-toluenesulphonic acids.

The invention further provides a pharmaceutical composition comprising a compound of general formula (II) or a pharmaceutically acceptable acid addition salt thereof 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 solid which is in admixture with the 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. Similarly cachets are include.

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, sweeteners, 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. fractioned 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 10% 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 compounds of the invention may be used in treating hypertension in a mammal in need of such treatment by administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The amount of compound used will depend on the activity of the compound and the needs of the mammal being treated. Doses may range from 0.1 to 50 mg/kg.The following Examples illustrate the invention: Example 1 N-(Yohimban- 77P-yllmethanesulphonamide a) Preparation of Yohimban-17-one oxime A mixture of yohimban-17-one (11.79g) and hydroxylamine hydrochloride (2.789; 1 equivalent) in ethanol (100 cm3) and pyridine (50 cm3) was stirred and heated to reflux for 7.5 hours After cooling the mixture was filtered, washed well with ethanol and dried to 80"C/100 mmHg to give crystals of yohimban-17-one oxime, hydrochloride, mp > 310 C (decomp. above 250 ) yield = 12.80 g.

b) Preparation of 17ss-aminoyohimban A suspension of the oxime from step a) (3.8g) in absolute ethanol (50cm3) was mechanically stirred and heated to reflux as small pieces of sodium (7g) were added over 3/4 hour. The mixture was refluxed for a further 4 hours, extra ethanol (30cm3) being added after 2 hours. The cooled mixture was then diluted with water (50 cm3) and the clear solution evaporated under vacuum until the ethanol had been removed.

The aqueous residue was diluted with water (75 cm3) and allowed to stand. The precipitated crystals of 17p-amino-yohimban were filtered off, washed with water and dried m.p. 234-245 (dec).

c) Preparation of N-(yohimban- 17p-yl) methanesulphonamide A suspension of 17p-aminoyohimban (from step b) 2.65g; 8.97mM) and triethylamine (1.0g, 9.9mM) in dichloromethane (50 cm3) was stirred at room temperature as a solution of mesyl chloride (1.039; 9.00mM) in dichloromethane (25 cm3) was added slowly. The clear solution was kept for 4 days, then washed with water 2 x cm3). A solid which separated was found to be identical to the major component of the organic phase. The organic phase was dried (MgSO4), filtered, evaporated and combined with the first solid. The mixture was dissolved in dimethylformamide, shaken with silica gel, excess solvent evaporated and the solid gel added to the head of a silica column made up in 10% ethanol-ethyl acetate.

Elution with this solvent mixture afforded the title product as a dark solid (1.679). Trituration with ethanol-ether gave a cream precipitate (1.27g) which was suspended in boiling ethanol (10 cm3), acidified with ethanolic hydrogen chloride and stirred well at room temperature for 2.5 hours to ensure complete conversion to the salt. Filtration and washing with ethanol gave the title compound as the hydrochloride, hemihydrate (1.249) as cream crystals, m.p. 260-270 (dec.).

Analysis Found: C, 57.68; H, 6.69; N, 9.74%.

C20H27N302S. HCl.1/2H3O requires C, 57.33; H, 6.98; N, 10.02%.

Example 2 N-Methyl-N-(yohimban-17ss-yl)methanesulphonamide (Route 1) An ice-cold mixture of N-(yohimban-17ss-yl)sulphonamide (from Example 1) (1.159; 2.81mM), water (25 cm3), dichloromethane (25 cm3), NaOH (0.07g; 17.5mM) and nBu4NHSO4 (0.07g; catalyst) was vigorously stirred as a solution of dimethyl sulphate (0.40cm3, 0.53g; 4.21mM) was added in one lot. The thick yellow slurry was stirred vigorously until two clear phases had formed (ca. 2h), and then for 3 days. The layers were separated, and the organic phase washed with brine (25cm3) and dried (MgSO4). Filtration and evaporation gave a yellow solid (0.839) which was purified by chromatography on silica eluted with 10-20% ethanol in toluene.The isolated product, a pale-yellow solid (0.51g), was triturated with boiling ethanol (12cm3), cooled, filtered and the solid suspended in ethanol and treated with ethanolic HC1. After stirring well, the crystals were collected by filtration and dried at 700/lmm to give the title compound as the hydrochloride, hydrate (0.32g; 25.8%) as colourless crystals, m.p. 270-290" (dec.) Analysis Found: C, 57.37; H, 7.23; N, 9.40% C2,H29N302.HCI.H2O requires C,57.06; H, 7.30; N, 9.51%.

Example 3 N-Methyl-N-(yohimhan- l7p-yl)methanesulphonamide Route 2 a) Preparation of 17ss-(N-methylamino)yohimbane. A slurry of yohimban-17-one (2.94; 0.01m) in toluene (30 cm3) and dichloromethane (100 cm3) was stirred at -20 C as several cm3 of MeNH2 were condensed in from a cylinder. The mixture was stirred well at between -10" to -20 C as TiC14 (0.7 cm3) in toluene (10cm3) was added slowly. The cooling-bath was removed, and the mixture stirred at room temperature overnight. The precipitate was filtered off and the reddish filtrate evaporated to give a pink glass (2.859). This was dissolved in ethanol (100cm3), treated with NaBH4 (1g), stirred and heated to reflux for 4 hours.After cooling, the solvent was evaporated and the residue taken up in water (250cm3). After extraction with chloroform (2 x 100 cm3), the combined organic layers were washed with water and dried (MgSO4). Filtration and evaporation gave crude 17ss-(N-methylamino)yohimbane (2.63g; 85%). This was used directly in the following experiment.

b) A solution of crude 17ss-N-methylamino)-yohimbane (2.69) and triethylamine (1.0g) in dichloromethane (50cm3) was treated at 0" with a solution of methanesulphonyl chloride (0.96g; 1 equiv) in dichloromethane (25cm3). The clear solution was kept at room temperature overnight, washed with water (2 x 50cm3) and dried (MgSO4). Filtration and evaporation gave a glass which was chromatographed on silica eluted with 20% v,v ethanol-ethyl acetate, to give the title compound base as a yellow solid (1.619). The base was converted to the hydrochloride in ethanolic HCI and triturated several times with ethanol. Filtration gave crystals of the title compound as the HCI salt monohydrate, (0.80g) after drying at 80 /100 mmHg. mp > 260 (dec.).

Claims (19)

1. A compound having the formula I

or a salt thereof, wherein R represents hydrogen or lower alkyl, Ri represents lower alkyl, haloloweralkyl, aryl, heteroaryl, or a group of formula R2R3N-A- wherein R2 and R3 independently represent hydrogen, lower alkyl, aryl or arylloweralkyl or R2 and R3 together with the nitrogen atom to which they are attached represent a ring selected from pyrrolidino, piperidino or morpholino; A represents a direct bond between the S and N atoms or a lower alkylene group having 1 to 3 carbon atoms between the S and N atoms, and R4 and R6 independently represent hydrogen or a substituent selected from halogen, lower alkyl and lower alkoxy.

2. A compound as claimed in Claim 1 wherein R' represents lower alkyl, haloloweralkyl, phenyl, pyridyl, thienyl, furyl, thiazolyl or phenyl substituted by one or more substituents selected from lower alkyl, halogen and lower alkoxy, or R1 represents a group of formula R2R3N-A- wherein R2 and R3 independently represent hydrogen, lower alkyl, phenyl, phenylloweralkyl wherein the phenyl substituents are one or more substituents selected from the group consisting of halogen, lower alkyl and lower alkoxy or R2 and R3 together with the nitrogen atom to which they are attached represent a ring selected from pyrrolidino, piperidino or morpholino.

3. A compound as claimed in Claim 1 or Claim 2 wherein A is methylene, ethylene, ethylethylene or propylene.

4. N-(Yohimban-17ss-yl)methanesulphonamide or a pharmaceutically acceptable salt thereof.

5. N-Methyl-N-(yohimban-17ss-yl) methanesulphonamide or a pharmaceutically acceptable salt thereof.

6. A compound as claimed in any one of claims 1 to 5 which is in the form of a salt formed from an acid selected from sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic and p-toluenesulphonic.

7. A process for preparing a compound of formula I as defined in Claim 1 which comprises reacting an amine of general formula II

with a reactive derivative of a sulphonic acid of general formula RlSO2OH (Ill) in which formulae R, Ra, R4 and Rs are as defined in Claim 1.

8. A process as claimed in Claim 7 in which the reactive derivative of the compound of formula Ill is the halide or anhydride.

9. A process for preparing a compound of formula I as defined in Claim 1 wherein R is lower alkyl which comprises alkylating a compound of formula I as defined in Claim 1 wherein R is hydrogen.

10. A process for preparing a compound of formula I as defined in Claim 1 in which Ri is R2R3N-Awhich comprises reacting a compound of general formula IV

where R, R4, R5 and A are as defined in Claim 1 and X is halogen, with ammonia or an amine of formula HNR2R3 wherein R2 and R3 are as defined in Claim 1.

11. A process for preparing a compound of formula las defined in claim 1 wherein R1 is R2R3N-Awherein A is a direct bond which comprises reacting a compound of formula II as defined in Claim 7 with a sulphonamide derivative of the formula

(where R2 and R3 have the meanings given in Claim 1.

12. A process for preparing a compound of formula I as defined in Claim 1 in which R1 is R2R3 N-Awherein A is a lower alkylene group of at least two carbon atoms which comprises reacting ammonia or an amine of formula (V)with a compound of formula (VII)

wherein R, R4 and Rs are as defined in Claim 1 and R7 is lower alkenyl.

13. A process for preparing a compound of formula I as defined in Claim 1 wherein R2 and/or R3 are/is lower alkyl or aryl(lower)alkyl which comprised alkylating or arylalkylating corresponding compounds of formula I wherein R2 and/or R3 is hydrogen.

14. A process for preparing a compound of formula I as defined in Claim 1 in free base form which comprises basifying an acid addition salt of a compound of formula

15. A process for preparing an acid addition salt of a compound of formula I which comprises acidifying a compound of formula I in free base form.

16. 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(c), 2 and 3(b).

17. A compound of formula I or a salt thereof as defined in Claim 1 whenever prepared by a process as claimed in any one of Claims 7 to 16.

18. A compound of formula I or a pharmaceutically acceptable salt thereof as defined in Claim 1 for use as a pharmaceutical.

19. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as defined in any one of Claims 1 to 6 and a pharmaceutically acceptable carrier.