ZA200208658B

ZA200208658B - Novel, slow-acting betamimetics, a method for their production and their use as medicaments.

Info

Publication number: ZA200208658B
Application number: ZA200208658A
Authority: ZA
Inventors: Kurt Schromm; Alexander Walland; Karl-Heinz Bozung; Hermann Willi Schollenberger
Original assignee: Boehringer Ingelheim Pharma
Priority date: 2000-04-27
Filing date: 2002-10-25
Publication date: 2003-10-14
Also published as: ECSP003424A

Description

", t WO 01/83462 . " ’ BOEHRINGER INGELHEIM PHARMA KG ® 74404pct.206

New betamimetics having a long-lasting activity, processes for preparing them and their use as medicaments

The present invention relates to new betamimetics of general formula 1

OH

PP

R' XOR

Me Me 1 wherein the groups R1 and R2 may have the meanings given in the claims and specification, processes for preparing them and their use as medicaments.

Background to the invention

Betamimetics (R-adrenergic substances) are known from the prior art. They may be used in a variety of therapeutic applications.

For drug treatment of diseases it is often desirable to prepare medicaments with a longer duration of activity. As a rule, this ensures that the concentration of the active substance in the body needed to achieve the therapeutic effect is present over a longer period of time without the need to administer the drug repeatedly, frequently.

The administration of an active substance at longer intervals of time also contributes considerably to the patient's wellbeing.

The aim of the present invention is to prepare betamimetics which are characterised by a longer duration of activity and can thus be used to prepare pharmaceutical compositions which have a longer-lasting activity.

Detailed description of the invention

Surprisingly, it has been found that the aim specified above is solved by compounds of general formula 1.

Accordingly the present invention relates to compounds of general formula 1

OH

PN

R' XOR

Me Me 1

® , wherein

R1 denotes a group

R® R* nog

HO . where

R3 denotes benzyl, which may optionally be substituted by methoxy;

R4 denotes hydrogen or

R3 and R4 together denote a -CO-CH-O- bridge, the carbonyl group of this bridge being bound to the nitrogen,

R2 denotes a group selected from and hey , SL

R°. while

RS denotes dimethylamino, methoxy or butoxy;

X denotes a nitrogen or a carbon,

RE denotes methoxyphenyl if X denotes nitrogen or denotes an anellated phenyl ring, which is also linked to X, if X denotes carbon.

Preferred compounds of general formula 1 are those wherein

R1 denotes a group selected from

MeO : SN

Lh and HN. _

HO HO :

= WO O01/83462 | ; BOEHRINGER INGELHEIM PHARMA KG ® 5

R2 denotes a group selected from @ a. QL 4

NMe, OMe 0 = IY a < bg and §

N

OMe

Particularly preferred are compounds of general formula 1 wherein

R1 denotes a group selected from

MeO

NT JS8

HO i i

R2 denotes a group selected from

Me

RO 0s and gy

Of particular importance according to the invention are compounds of formula 1, wherein

R1 denotes a group

R® R* a

HO : wherein

R3 and R4 together denote a -CO-CH2-O- bridge, the carbonyl group of this bridge being bound to the nitrogen,

‘ . te WO 01/83462 . . ' BOEHRINGER INGELHEIM PHARMA KG .

R2 denotes a group selected from he, and

C Ju § A, wherein

RO denotes dimethylamino, methoxy or butoxy;

X denotes a nitrogen or a carbon,

RE denotes methoxyphenyl if X denotes nitrogen or an anellated phenyl ring which is also linked to X, if X denotes carbon.

Preferred compounds of general formula 1 are those wherein

R1 denotes oe

HO :

R2 denotes a group selected from

Id . TL. AN ~N a and N

OMe

Of equivalent importance according to the invention are compounds of formula 1, wherein

R1 denotes a group

R°® R* [

Yr

HO . wherein

R3 denotes benzyl which may optionally be substituted by methoxy;

". AR WO 01/83462 . ve , BOEHRINGER INGELHEIM PHARMA KG

R4 denotes hydrogen;

R2 denotes the group pe

EN wherein

X denotes a nitrogen or a carbon,

Of outstanding importance according to the invention are the following compounds of formula 1: - 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2- methyl-2-butylamino]ethanol, - 1-[2H-5-hydroxy-3-ox0-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N- dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, - 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2- methyl-2-propylaminolethanol.

In the compounds of formula 1 according to the invention R1 may denote the group

R® R* poy

HO and preferably one of the groups

MeO 0)

Le and

HN HN. 5

HO HO

Of the compounds of formula 1 according to the invention the ones which are particularly preferred are those wherein the hydroxyl group in the abovementioned

= W0o01/83462 ) BOEHRINGER INGELHEIM PHARMA KG groups Ris in the ortho or meta position relative to the amino substituent. Most preferably, the hydroxy group is in the ortho position to the amino group.

The invention relates to the compounds of formula 1_optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates as well as in the form of the free bases or the corresponding acid addition salts thereof with pharmacologically acceptable acids — such as, for example, acid addition salts with hydrohalic acids - for example hydrochloric or hydrobromic acid - or organic acids such as acetic, oxalic, fumaric, diglycolic or methanesulphonic acid.

Of the acid addition salts mentioned above the salts of hydrochloric, methanesulphonic and acetic acid are particularly preferred according to the invention.

The compounds according to the invention may be prepared, as described below, partly analogously to procedures which are already known in the prior art (Diagram 1).

Q 0

Ro .\ INS >r? - 5 CNP Re 0 Me Me i Me” “Me 2 3 4

OH H

RA— RE

Me Me 1

Diagram 1:

Starting from suitably substituted aldehydes 2, which may optionally be present in the form of their hydrates, the reaction is carried out with the amines 3 to form the

Schiff's bases of formula 4. Methods of forming Schiff's bases are known from the prior art. These Schiff's bases are finally reduced to form the compounds of formula 1 according to the invention. This reduction may be carried out, for example, with metal salt hydrides of the sodium borohydride type analogously to known standard methods. It may possibly be necessary to use protecting groups (e.g. a benzyl protecting group). Their use and subsequent removal are known to those skilled in the art.

cL . WO 01/83462 . “ . BOEHRINGER INGELHEIM PHARMA KG ® :

The Examples of synthesis described below serve to illustrate the present invention further. They must only be taken as examples of procedure, to illustrate the invention further, without restricting the invention to the object described below by way of example.

Example 1: 1-[2H-5-hydroxy-3-ox0-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N- dimethylaminophenyl)-2-methyl-2-propylaminolethanol: “No OH

HO NMe,

Preparation of the Schiff's base (compound of formula 4) 19.1 g (0.058 mol) of [2H-5-benzyloxy-3-oxo0-4H-1,4-benzoxazin-8-yl]-glyoxal hydrate are added to a solution of 250 ml of ethanol and 9.6 g (0.05 mol) of 3-(4-

N,N-dimethylaminophenyl)-2-methyl-2-propylamine heated to 70°C and stirred for 15 minutes. After cooling the crystals precipitated are suction filtered and dried.

Yield: 24 g = 99% of theory; melting point = 201 — 204°C.

Reduction of the Schiff's base to obtain 1-[2n-5-benzyloxy-3-oxo0-4H-1,4-benzoxazin- 8-yl]-2-[3-(4-N,N-dimethylamino-phenyl)-2-methyl-2-propylamino]-ethanol: 24 g of the Schiff's base (0.0495 mol) are suspended in a mixture of 120 mi of ethanol/120 ml of dioxane and combined with 2 g of NaBHg4 within 30 minutes at 10- 20°C and stirred for one hour. After the addition of 10 ml of acetone the mixture is stirred for 30 minutes, diluted with 300 ml of ethyl acetate, the ethyl acetate phase is washed twice with about 200 ml of water, dried with sodium sulphate and the solvent is distilled off in vacuo. The dihydrochloride is isolated from the residue with alcohol/acetone by acidifying with conc. hydrochloric acid and suction filtered.

Yield: 17.5 g = 62.6 % of theory; melting point = 180 — 185°C.

Cleaving of the protecting group to obtained the title compound: 3.5 g of the benzyl compound obtained above (0.0066 mol) are hydrogenated in 75 ml of methanol with the addition of 0.5 g of Pd/C at ambient temperature and normal pressure. The catalyst is suction filtered, the filtrate is evaporated down, screened and the crystals precipitated are separated off.

Yield: 2.4 g = 82.8 % of theory; melting point = 216 — 218°C (hydrochloride).

® 6

Example 2: 1-[2H-5-hydroxy-3-o0x0-4H-1,4-benzoxazin-8-yl}-2-[3-(4-n- butyloxyphenyl)-2-methyl-2-propylamino]ethanol: © 0 OH

YO H

Me M

HO © ve 07 "Me

The title compound is prepared analogously to the method in Example 1.

Melting point = 189-190°C (methanesulphonate).

Example 3: 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1- benzimidazolyl)-2-methyl-2-butylaminolethanol:

MeO ra Me

HO

The title compound is prepared analogously to the method in Example 1.

Melting point = 154-155°C (acetate).

YO ‘

HN N

HO OMe

The title compound is prepared analogously to the method in Example 1.

Melting point = 202-205°C (hydrochloride).

a. .. WO 01/83462 . . BOEHRINGER INGELHEIM PHARMA KG ® 0

Example 5: 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4- methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol:

NT H _N

Oo I 2 Sone

WN

Me Me

OH

The title compound is prepared analogously to the method in Example 1.

Melting point = 175-179°C (hydrochloride).

As has been found, the compounds of general formula 1 are characterised by their range of uses in the therapeutic field. Particular mention should be made of those applications for which the compounds of formula 1 according to the invention may preferably be used on the basis of their pharmaceutical activity as betamimetics.

These include, for example, the treatment of bronchial asthma (relaxation of the bronchial muscle), the treatment of the inflammatory component in COPD, the inhibition of premature labour in midwifery (tocolysis), the restoration of the sinus rhythm in the heart in cases of atrio-ventricular block as well as the correcting of bradycardiac heart rhythm disorders (antiarrhythmic agent), the treatment of circulatory shock (vasodilatation and increasing the heart-time volume) as well as the treatment of itching and skin inflammation.

The compounds of general formula 4 may be used on their own or in conjunction with other active substances of formula 1 according to the invention. If desired the compounds of general formula 1 may also be used in conjunction with other pharmacologically active substances.

These may be, in particular, anticholinergics, possibly other betamimetics, antiallergics, PAF antagonists, leukotriene antagonists and steroids as well as combinations of active substances.

Examples of anticholinergics which may be mentioned include ipratropium bromide, oxitropium bromide and particularly tiotropium bromide. Drug combinations which contain tiotropium bromide as an additional active substance as well as the compounds of formula 1 according to the invention are particularly preferred according to the invention. This combination is particularly important in the treatment of asthma or COPD, particularly COPD.

. Lo WO 01/83462 , BOEHRINGER INGELHEIM PHARMA KG ® 10

Suitable preparations for administering the compounds of formula 1 include for example tablets, capsules, suppositories, solutions, etc. The content of the pharmaceutically active compound(s) should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-% of the composition as a whole. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.

The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers.

Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.

® .

Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

The preparations are administered by the usual methods, preferably by inhalation in the treatment of asthma or COPD. For oral administration the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.

The dosage of the compounds according to the invention is naturally highly dependent on the method of administration and the complaint which is being treated.

When administered by inhalation the compounds of formula 1 are characterised by a high potency even at doses in the ug range. The compounds of formula 1 may also be used effectively above the ug range. The dosage may then be in the gram range, for example.

The examples of formulations which follow illustrate the present invention without restricting its scope:

Examples of pharmaceutical formulations

A) Tablets per tablet active substance 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15mg magnesium stearate 5mg 500 mg

The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

B) Tablets per tablet active substance 80 mg lactose 55 mg corn starch 190 mg microcrystalline cellulose 35mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2mg 400 mg

The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodium carboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.

® 3

C) Ampoule solution active substance 50 mg sodium chloride 50 mg water for inj. 5mi

The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

D) Metering aerosol active substance 0.005 sorbitan trioleate 0.1 monofluorotrichloromethane and difluorodichloromethane 2:3 ad 100

The suspension is transferred into a conventional aerosol container with a metering valve. Preferably, 50 pl of suspension are delivered per spray. The active substance can also be in a higher dose if desired (e.g. 0.02 wt.-%).

E) Solutions (in mg/100ml) active substance 333.3 mg tiotropium bromide 333.3 mg benzalkonium chloride 10.0 mg

EDTA 50.0 mg

HCI (1N) ad pH 3.4

This solution can be produced in the usual way.

F) Inhalable powder active substance 6 ug tiotropium bromide 6 ug lactose monohydrate ad 25 mg

® 14

The inhalable powder is prepared in the usual way by mixing the individual ingredients together.

Claims

Patent Claims 1) Compounds of general formula 1 OH PW R' KOR Me Me 1 wherein R denotes a group RP R as HO where R3 denotes benzyl, which may optionally be substituted by methoxy;

R4 denotes hydrogen or

R3 and R4 together denote a -CO-CH»-O- bridge, the carbonyl group of this bridge being bound to the nitrogen, R2 denotes a group selected from

N— and i¢ , § A,

while

RS denotes dimethylamino, methoxy or butoxy;

X denotes a nitrogen or a carbon,

RE denotes methoxyphenyl if X denotes nitrogen or denotes an anellated phenyl ring, which is also linked to X; if X denotes carbon.

. i. WO 01/83462 : : BOEHRINGER INGELHEIM PHARMA KG @® T: 2) Compounds of general formula 1 according to claim 1, wherein R1 denotes a group selected from MeO

HN. : _ and HN. > _ HO HO R2 denotes a group selected from Id ROW . AGN Bn IY & { 3g and N N OMe 3) Compounds of general formula 1 according to one of claims 1, 2 or 3, wherein R1 denotes a group selected from MeO NO JS§ .

HN. : and HN. > _ HO HO : R2 denotes a group selected from Me

® 17 4) Compounds of formula 1 according to claim 1, wherein R1 denotes a group R® R* ang HO : wherein R3 and R4 together denote a -CO-CHy-O- bridge, the carbonyl group of this bridge being bound to the nitrogen, R2 denotes a group selected from and , § A wherein RS denotes dimethylamino, methoxy or butoxy; X denotes a nitrogen or a carbon, RG denotes methoxyphenyl if X denotes nitrogen or an anellated phenyl ring which is also linked to X, if X denotes carbon. 5) Compounds according to general formula 1 according to claim 1 or 4, wherein R1 denotes No nos

HO . R2 denotes a group selected from el. WO 01/83462 BOEHRINGER INGELHEIM PHARMA KG @® 18 Id RO pO AGN nN & and N OMe 6) Compounds according to general formula 1 according to claim 1, wherein R1 denotes a group R’ rR* Bo

HO . wherein R3 denotes benzyl which may optionally be substituted by methoxy; R4 denotes hydrogen; R2 denotes the group TM i NBN 6

R’. wherein X denotes a nitrogen or a carbon, R6 denotes methoxyphenyl if X denotes nitrogen or an anellated phenyl ring which is also linked to X, if X denotes carbon. 7) Compounds of general formula 1 according to one of claims 1 to 6, characterised in that the hydroxy group in the group R1is in the ortho or meta position to the amino group. 8) 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2- methyl-2-butylamino]ethanol.

are WO 01/83462 . : BOEHRINGER INGELHEIM PHARMA KG

9) 1-[2H-5-hydroxy-3-ox0-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N- dimethylaminophenyl)-2-methyl-2-propylamino]ethanol.

10) 1-[2H-5-hydroxy-3-0x0-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2- methyl-2-propylamino]ethanol.

11) Compounds of formula 1_ according to one of claims 1 to 10 in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates as well as in the form of the free bases or the corresponding acid addition salts thereof with pharmacologically acceptable acids.

12) Use of a compound of general formula 1 according to one of claims 1 to 11 as a medicament.

13) Use of a compound of general formula 1 according to one of claims 1 to 11 for preparing a pharmaceutical composition for treating complaints in which betamimetics may have a therapeutic benefit.

14) Use of a compound of general formula 1 according to one of claims 1 to 11 for preparing a pharmaceutical composition for treating bronchial asthma (slackening of the bronchial muscle), the inflammatory component in COPD, premature onset of labour in midwifery (tocolysis), atrio-ventricular block as well as bradycardiac hearth rhythm disorders (antiarrhythmic), circulatory shock (vasodilatation and increasing the heart time volume) and itching and inflammation of the skin.

15) Pharmaceutical preparations containing as active substance one or more compounds of general formula 1 according to one of claims 1 to 11 optionally combined with conventional excipients and/or carriers.

16) Pharmaceutical preparations according to claim 15, characterised in that they also contain, in addition to one or more of the compounds of formula 1, at least one other active substance which is selected from among the anticholinergics, betamimetics, antiallergics, PAF antagonists, leukotriene antagonists and steroids.

17) Pharmaceutical preparations according to claim 16, characterised in that they also contain tiotropium bromide as active substance, in addition to one or more of the compounds of formula 1.