CA1331005C - Pyridylethanolamines, pharmaceutical compositions containing them and processes for their preparation - Google Patents
Pyridylethanolamines, pharmaceutical compositions containing them and processes for their preparationInfo
- Publication number
- CA1331005C CA1331005C CA000576154A CA576154A CA1331005C CA 1331005 C CA1331005 C CA 1331005C CA 000576154 A CA000576154 A CA 000576154A CA 576154 A CA576154 A CA 576154A CA 1331005 C CA1331005 C CA 1331005C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Diabetes (AREA)
- Engineering & Computer Science (AREA)
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- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
- Hydrogenated Pyridines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Pyridylethanolamines Abstract The invention relates to compounds of formula I
Description
~.
Pyridylethanolamines The present invention relates to new pyridylethanol-amines, processes for thei~ preparation and pharmaceu-tical compositions containing them.
We have found that certain novel pyridylethanolamines exhibit valuable pharmacological properties, partic-ularly an effect on metabolism, especially an effect of reducing blood sugar and body fat, and the effect of reducing levels of the atherogenic lipoproteins VLDL and LD~,. Some of the compounds mentioned also have an anabolic activity.
Thus according to one aspect the present invention provides compounds of formula I
ClJ~CH-cH2_ (wherein R represents a carboxymethoxy, carbomethoxymethoxy, ethoxycarbonylmethoxy or 2-bydroxyethoxy group), and the optical isomers, diastereoisomers and acid addition salts thereof.
The compounds of ormula I may form salts, e.g. ~ -wlth inorganic or organic acids, the particularly preferred salts being those which are physiologically acceptable.
1331 ~0~ -:
Pyridylethanolamines The present invention relates to new pyridylethanol-amines, processes for thei~ preparation and pharmaceu-tical compositions containing them.
We have found that certain novel pyridylethanolamines exhibit valuable pharmacological properties, partic-ularly an effect on metabolism, especially an effect of reducing blood sugar and body fat, and the effect of reducing levels of the atherogenic lipoproteins VLDL and LD~,. Some of the compounds mentioned also have an anabolic activity.
Thus according to one aspect the present invention provides compounds of formula I
ClJ~CH-cH2_ (wherein R represents a carboxymethoxy, carbomethoxymethoxy, ethoxycarbonylmethoxy or 2-bydroxyethoxy group), and the optical isomers, diastereoisomers and acid addition salts thereof.
The compounds of ormula I may form salts, e.g. ~ -wlth inorganic or organic acids, the particularly preferred salts being those which are physiologically acceptable.
1331 ~0~ -:
According to a further aspect, the present invention ;
also provides a process for the preparation of compounds of the invention, said process comprising at least one of the following steps: -(a) reacting a compound of formula II
:' ', H
Y - N - Y (II) (wherein one of the moieties Y represents a hydrogen - :
atom and the other represents a group of formula ~ ~
~ OH , 3 ~ -Cl N CH-CH2- - CH - CH2 ~ R ~ -~
' -wherein R is as hereinbefore defined~
with a compound of formula III :
':, : - -Zl U (III) (wherein U represents a group of formula , CH
or - , 3 ~
-CH2-CH ~ N ~ Cl -cH-cH2 ~ R
o~r '~ ' ' '' wherein R is as hereinbefore defined, and .: ': ,' ','~, Zl and V together represent a bond, or ;-- 133100$
!
Zl represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a sulphonyloxy group, e.g. a methane-sulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyl-oxy group and V represents a hydrogen atom) (b) reductively aminating a carbonyl compound of formula IV
- ,~
CH3-CO-cH2 ~ R ~
:,~: : : :' Iwherein R i8 a~ hereinbefore defined) ~; with an amine of formula V
. . .~..
ON ~ X , . - :~.~;
Cl N CH-~H2-N
c) reducing a compound of formula VI
ClJ~CO-CN2-N-CX-CXz~R ~ ~
~:: :: :,.; ` . :
.,., . ..,,..,:,,- ~ .-:
= ~:
~ 3 3 1 0 a 3 (wherein R is as hereinbefore defined); -:
(d) reacting a compound of formula VII
-CHrN--CH-CH2~0H
with a compound of formula VIII
:
Z2 ~ Rl (VIII) :, ; ..
(wherein .;: -: Rl represents a carboxymethyl, methoxycarbonyl- ~ :
methyl, ethoxycarbonylmethyl or 2-hydroxy-ethyl -.
group, and Z2 represents a nucleophilic ieaving group such as a halogen atom or a sulphonyloxy group, e.g. ~ :
a chlorine, bromine or iodine atom or a methanesul-phonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy ~" : group, or " , :
Z2 together with a ~-hydrogen atom of the group Rl represents an oxygen atom);
., - ~ ..
e) hydrolysing a resulting compound of formula - ..
I wherein R represents a methoxycarbonylmethoxy or ethoxycarbonylmethoxy group to yield a corresponding . ::
compound of formula I wherein R represents a carboxy- .
methoxy group; : -:
:..: ' ~) converting a compound of formula I into an acid addition salt thereof, or an acid addition ,~,x,., ~,",~" ~
1 3 31 ~ 0 S
salt of a compound of formula I into the free base;
and (g) resolving a resulting compouna of formula I or a salt thereof into its aiastereomers or enant- r iomers.
The reaction of step (a) may conveniently be carried out in a solvent or mixture of solvents such as methanol, ethanol, acetone, diethylether, methyl- - -formamide, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetra~
hyarofuran, dioxan or in an excess of the compound ~ --of formula III used. Optionally the reaction is -~
effected in the presence of an acid binding agent, -e.g. an allcoxide such as potassium tert.butoxide, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as soaium ~-amide, an alkali metal hydride such as ~odium hydride, a tertiary organic base~such as triethylamine, N,N-diisopropylethylamine or pyridine, where the latter may also be s1multaneously used as solvent, or in the presence of a reaction accelerator such potassium iodide. The reaotion is conveniently ` ~ -effected at temperatures between O and 150-C, depending ;~ -on the reactivity of the nucieophilically exchangeable ~`~
group, preferably at a temperature between SO u and 120C, e.g. at the boiling temperature of the solvent u~ied, The reaction may, howëver,~also be carried out without a solvent. It is particularly advantageous to carry out the reaction with a corres~
ponding epoxide of formula III without the addition ; ` ;`
of an acid binding agent. `-'~
The reductive amination of step ~b) may be carried `~
out in a ~olvent such as methanol, ethanol, tetra-? ,`
~331~
hydrofuran, dioxan or acetonitrile in the presence of a reducin~ agent such as a complex metal hydride, but preferably in the presence of sodium cyanoboro-hydride at a p~ of from 5 to 7, and conveniently at temperatures of between 0 and 50C, but preerably at ambient temperature.
The reduction of step (c) may preferably be carried out in a solvent such as methanol, ethanol, diethylether or tetrahydrofuran in the presence of a metal hydride such as sodium borohydride, lithium aluminium hydride, diborane, borane/dimethylsulphide or sodium cyanoboro-hydride, but preferably with sodium borohydride in methanol or ethanol and conveniently at temperatures between 0 and 40C, but preferably at ambient témper-ature. -When the reduction of step ~c) is carried out with a complex metal hydride such as lithium aluminium hyaride, diborane or borane/dimethylsulphiae, a carbonyl function present in the group R may be reducea at the same time to yield a methylene group. ~ -The reaction of step ~d) may conveniently be carried out in a solvent such as diethylether, tetrahydrofuran, dioxan, methanol, ethanol or dimethylformamide ana preferably in the presence of an acid-binaing --~
agent such as soaium hydroxide or potassium tert.but-oxide, but preferably in the presence of potassium carbonate or soaium hydriae or pyridine, whilst an organic base such as pyridine may also be use as solvent, or, in order to prepare 2-hydroxy-ethoxy -~
compounas of formula I, with ethylene oxide. The reaction conveniently is effected at temperatures of between 0 and 100C, preferably at temperatures of between 20 and 80C.
::
1331~0~
In the reactions of steps (aJ to (d) described above, reactive groups may be protected during the reaction with conventional protecting groups which are then split off again by conventional methods after the reaction.
Examples of suitable protective groups for a carboxy group include benzyl, tert.butyl, tetrahydropyranyl, trimethylsilyl, benzyloxymethyl, 2-chloroethyl and methoxymethyl groups and a phenacyl group, e.g. a benzoylmethyl group, suitable protecting ~ --groups for an amino or alkylamino group include ~-acetyl, benzoyl, tert.butoxycarbonyl, benzyloxycar~
bonyl, ethoxycarbonyl and benzyl groups and suitable ~ ~ -protecting groups for a hydroxy group include, for example, trityl, fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzyl groups. --. : ~, : ~,:
~, . .; ....
The optional subsequent splitting off of any protecting group used is preferably carried out by hyarolysis in an aqueous solvent, e.g. in water, isopropanol/
water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as hydrochloric or sulphuric acid or in the presence of an alkali ~ `;
metal base such as sodium hydroxide or potas~ium ;;-~
hydroxide, conveniently at temperatures of between 0 and 100C, preferably at the boiling temperature of the reaction mixture. A benzyl or benzyloxycarbonyl group, however, is preferably removed by hydroqenoly-Si8, e.g. with hydroqen in the presence of-a catalyst such as palladium/charcoal in a solvent such as -;
methanol, ethanol, etbyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, conveniently at temperatures of between 0 and 50C, but preferably at ambient temperature, under a hydrogen pressure of from l to 7 bar, but preferably from 3 to S bar.
',:'-'.,`,'..' :` 133~
The hydrolysis of step (e) is carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, ethanol, ethanol/water, water/iso-propanol or water/dioxan, conveniently at temperatures of between -10C and 120C, e.g. at temperatures of between ambient temperature and the boiling temperature of the reaction mixture.
The compounds of formula I obtained may be converted into the acid addition salts thereof, more particularly for pharmaceutical use the physiologically acceptable salts with inorganic or organic acids. Suitable acids for salt formation include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, fumaric, succinic, lactic, citric, tartaric and maleic acid.
As already mentioned hereinbefore, the compounds of formula I may occur in the form of the enantiomers, enantiomer mixtures or racemates thereof or in the form of pairs of diastereoisomers or mixtures - -of pairs of diastereoisomers.
Thus, the compounds of formula I obtained may be separated into their diastereoisomers on the basis of their physical/chemical differences by methods known Per se, e.g. by chromatography and/or fractional crystallisation. A pair of enantiomers thus obtained - ~-~
may then be separated into the optical antipodes thereof by methods known Per se (see Allinger N.L.
and Eliel E.L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), e.g. by recrystal-lisation from an optically active solvent or by reaction with an optically active substance which ~33~ 00~
g forms salts with the racemic compound, particularly an acid, and separation of the salt mixture obtained ~ -in this way, e.g. on the basis of differences in solubility, into the diastereomeric salts, from which the free antipodes can be liberated by the action of suitable agents. Optically active acids which are particularly useful include the D and ~ - -L forms of tartaric acid, di-o-toluene tartaric acid, malic acid, mandelic acid, camphor sulphonic acid, glutamic acid, aspartic acid and quinic acid.
The compounds used as starting materials which may, obviously, also be used in their optically pure forms, may be obtained by methods known from the literature (see ~Thiazole and its Derivativesn in Heterocyclic Compounds, Vol. 34, and Advances - -~
in Heterocyclic Chemistry, Vol 17, page lOOff (1974)) p~ --or are known from the literature. In some cases these compounds are only present in the reaction mixture and therefore cannot be isolated. ~ ~ ~
An intermediate compound of formula II, V, VI or - -VII may be obtained by corresponding alkylation of a suitable amine, e.g. as discussed in EP-A-239815.
An intermediate compound of formula III wherein Zl represents a nucleophilic leaving group maybe ~ ~-obtained by reduction of a corresponding acetyl compouna, e.g. with a complex metal hydride, or -by conversion of a corresponding hydroxy compound into a reactive derivative tbereof.
''-''''.'- :
An epoxide of an intermediate compound of formula III may be obtained for example by reacting a suitable bromo- or tosylethanol with aqueous potassium or sodium hydroxide ~olution.
' ' ' ~::
', ~
: 133100~
AS already mentioned hereinbefore, the compounds of formula I, the enantiomers, mixtures of enantiomers or racemates thereof or, if they contain at least 2 asym-metric carbon atoms, the diastereoisomers or mixtures of diastereoisomers, and the acid addition salts thereof, more particularly for pharmaceutical use the physiologically acceptable acid addition salts thereof, have valuable pharmacological properties, including, in addition to the effect of inhibiting platelet aggre-gation, an effect on the metabolism, especially an effect of lowering blood sugar and reducing body fat, and the effect of reducing the atherogenic ~-lipopro-teins VLDL and LDL. Moreover, some of the compounds mentioned above also have an anabolic activity.
The biological properties of the new compounds ~ -were investigated as follows:
1. Antidiabetic activitv .
The antidiabetic activity of the compounds according to the invention can be measured as a blood sugar-reducing effect in experimental animals. The test substances were suspended in 1.5% methyl cellulose and aaministered to laboratory-bred fema~e mice by oesophageal tube. 30 minutes later, 1 g of glucose per kg of body weight was dissolved in water and administered subcutaneously. After another 30 minutes, blood was taken from the retroorbital plexus venosus.
The level of glucose in the serum was determined by the hexokinase method using an analytical photometer.
In the Table which follows, the reductions in blood sugar observed in this experimental arrangement are shown as the percentage of a parallel control group.
Statistical evaluation was carried out by the Students t test taking p=0.05 as the limit of significance.
:~ 13310~
Compound ~i Change from the level of (Example No. ) the control group aosage [mg/kg]
O.l 0.3 l.O
l -66 2. Anti-adiPose activitY ~ ~
~ , The anti-adipose activity of the compounas according to the invention was demonstratea by two experimental arrangement a) In the first experiment the increase in lipolysis ~ ~ ~
was measurea by the increase in glycerol in the serum. ~ ~;
The experimental procedure 1s identical to the experi-mental arrangement described above for testing the reauction in blood sugar. The glycerol level was determined in a combined enzymatic/colorimetric test using an analytical photometer. The results are shown in the followlng Table as the percentage of a parallel control group.
Compound~i Change from the level of Example No.) the control group aosage [mg/kg]
, O.l 0.3 l.O
l +882 2 1454 ` ~ -3 +309 878 -~; ~
SA ;
",~
. . , ',' ;'-',..' "; ,,-, ~` 1331~0~
b) In the second experimental arrangement for determining the anti-adipose effect of the compounds according to the invention, the reduction in fatty tissue was measured on the fatty tissue of the ovary by way of example. For this purpose, the compounds were administered to mice once a day by oesophageal tube in a 1.5% methylcellulose suspension. On the fifth day the fatty tissue of the ovary was dissected out and weighed. The following Table shows the results -as a percentage of a parallel control group.
Compound % Change from the level of the con-~Example No.) trol group Dosage: 0.3 [mg/kg]
~ 5~ -54 3. Cardiac side effects The compounds of the invention have been shown to have no undesirable siae effects on the heart in the thera-peutic aosage range which has an effect on the metabo-lism. The evidence for this was provided by the measurement of heart rate in mice during the tests for the blood sugar reducing effect (see above). One hour after oral administration of the compounas heart rate was determined by means of an ECG-triggered tachograph.
The Table which follows shows the change in heart rate -~-as a percentage of the control group.
Compound% Change from the level Dosage ~Example No.) of the control group - ;
3 ~35 10 mg~kg 2 (+6.9) 0.3 mg/kg 27) 0.3 mg/kg .
L;.. ~ ~ - , . . . : : . . : , -: . . ,: . . : .-133~
The figures in brackets are not significant (p greater than 0.05) Furthermore, in the tests on the substances according to the invention described above, no toxic side effects were observed at the dosages used. The substances are therefore well tolerated.
In view of their pharmacological properties, the compounds of formula I and the physiologically --acceptable acid addition salts thereof are therefore suitable for the treatment both of diabetes mellitus and also obesity, particularly for treating obese diabetics. Moreover, the new compounds may be used for the prophylaxis and treatment of athero- -sclerotic changes in the blood vessels, which occur particularly in diabetics and obese people. The -dosage required can be matched entirely to the metabolic physiological requirements of the individual patients since the substances are free from any - -effect on the heart or circulation over a wide -~
aosage range. In adults, therefore, the daily dose may be between l and 3000 mg, but preferably 1 to 1000 mg, divided up into 1 to 4 doses per day. For this purpose, the above-mentioned compounds may be incorporated in conventional galenic prepa- ``
rations such as powders, tablets, coated tablets, capsules, suppositories or suspensions, optionally in conjunction with other active substances.
,:,, , . :Thus, in another aspect, the invention provides - -~
a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable acid ~-addition salt thereof together with at least one ~ -~
pharmaceutical carrier or excipient. It will be understood that the "pharmaceutical compositions~
,.. ::.- . - - . : , , , ~, .. , ,. ,, ,:: :. ., : . . , :,, , ,. ,, ,, . - , . . . .
1 3 ~
of the invention include within their scope compositions suitable -~
for administration to non-human animals, i.e. veterinary composi-tions.
In a still further aspect, the invention provides a method of treatment of the human or non-human body to combat diabetes mellitus, obesity and athero6clerosis comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
In a yet further aspect, the invention provides the use of a compound of formula I or a physlologically acceptable salt thereof for the preparation of a therapeutic agent for use in the treatment of diabetes mellitus, obesity and atherosclerosis.
In a still further aspect of the invention there is provided a commercial package containing as active pharmaceutical ingredient a compound of formula I or a physiologically acceptable salt thereof, together with instructions for the use thereof in the treatment of diabetes mellitus, obesity and atherosclerosis. -The compounds of the invention may thus also be used to treat overwelght animals such as dogs and, as a consequence of their body fat-reducing (lipolytic) effect, and they may be used to reduce undesirable fat deposits in the fattening of animals, i.e. in order to improve the quality of meat of fattened animals ! . such as pigs, cattle, sheep and poultry. In animals, the above-mentioned compounds may be administered by oral or non-oral routes, e.g. as a feed additive or by injection or by means of ;-implanted minipumps. The daily dose is between 0.01 and 100 mg~kg, preferably between 0.1 and 10 mg/kg of body weight.
B ~ ~-1331~û~
In a still further aspect the invention thus also provides an animal feed comprising a compound of formula I or a -~
physiologically acceptable salt thereof together with a feedstuff.
The Examples which follow are provided to illustrate the ~-~
invention without restricting its scope in any way.
Unless otherwise stated all percentages, parts and ratios referred to herein are by weight.
, ~,. ... ..
-',. -:
,-.~;, . - .
. ,,, ~ , .
. . :.: -- :
~,: . ,,:
.,,.". ;~,:,,, '''"~
-.,- .
: -~ .. , .-.
'.'.'' :".' '.: .,-'' ~ ' ' '., . :- ' : '" ' ' '''.' .: ~' ,~'.
, ,, , " ~:
.~
.:. .~ ,. .:~" ~:
~ " ~ ", 1331~û~
Example 1 N-[ 2-(4-CarbomethoxYmethoxyphenyl)-l-methylethyl]-2-hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine-hYdro-chloride .
0.23 g (0.00133 mol) of 2-hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine and 0.3 9 (0.00133 mol) of 1-(4-carbomethoxymethoxyphenyl)propan-2-one are dissolved in 15 ml of absolute methanol, O.Q8 9 (0.00133 mol) of glacial acetic acid and 0.084 9 (0.00133 mol) of sodium cyanoborohydride are added and the mixture is stirred for 16 hours at ambient temperature.
It is then p~ured onto ice and acidified with hydro-chloric acid. After 5 minutes it is made alkaline with ammonia at 0 to 5C and extracted with methylene chloride. The extract is dried over sodium sulphate and concentrated by evaporation and purified over a silica gel column using ethyl acetate/methanol (9:1) as eluant. The base i8 converted into the hydrochloride using ethereal hydrochloric acid.
Yield: 0.276 9 (46~ of theory), Melting point: from 70C (decomposition).
Calculated: C 54.94 H 5.~2 N 6.74 Cl 17.07 Found: 54.60 6.00 7.00 17.40 According to l~-NMR spectrum (400 MHz, DMSO/CD30D) an approximately 1:1 mixture of the pairs of aiastereo-isomers is present.
delta = 1.17 ppm (d,~ CH-CH3) delt~ - 1.20 pp~ (d,> 0 -~d3) .- :' -~ ~
~,~"~
~3310~
Example 2 ~ -.: .
N-[2-(4-(2-Hydroxyethoxy~phenyl)-l-methylethyl]-2- , ' ~ , hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine-hydro-chloride Prepared analogously to Example 1 by reacting 2- -hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine with - ~ - `
1-(4-(2-hydroxyethoxy)phenyl)propan-2-one and sodium ;
cyanoborohydride and subsequently purifying the -product over a silica gel column using ethyl acetate/- ~ -methanol (9:1) as eluant. The base is converted - --into the hydrochloride using ethereal hydrochloric acid. ;-Yield: 65~ of theory, Melting point: 68C ~decomposition) ~ ~-Calculated: C 55.81 H 6.24 N 7.23 Cl 18.30 Found: 55.60 6.46 7.09 18.47 -~
According to H-NMR spectrum (400 M~z, d6-DMS0/CD30D) -an approximately 1:1 mixture of the pairs of diastereo-isomers i8 present.
delta = 1.121 ppm (d,> CH-CH3) ~-delta = 1.136 ppm (d,~ CH-CH3) -~
ExamPle 3 -~
N-[2-(4-CarboxYmethoxYPheny~ -methylethyll-2 hyaroxy-2-~6-chloro-pvridin-2-Yl)ethanamine ,. . .
3.6 g (0.0095 mol) of N-12-(4-carbomethoxymethoxy-phenyl)-l-methylethyl]-2-hydroxy-2-~6-chloro-pyridin-2-yl)ethanamine are dissolved in 20 ml of methanol and 50 ml tO.05 mol) of lN sodium hydroxide solution are added. The solution iæ stirred for 30 minutes at ambient temperature and then neutralised with 50 ml of lN hydrochloric acid (0.05 mol). The solvent is distilled off in vacuo and the residue - ;
1 3 3 1 0 ~ 5 - 18 - ;
is stirred with 20 ml of water and 20 ml of methanol for 16 hours, suction filtered and washed with a little methanol.
Yield: 1.8 g ~52% of theory), Melting point: 218C ~decomposition).
Calculated: C 59.25 H 5 . 80 N 7.68 Found: 59.47 5.83 7.5s According to 1H-NMR spectrum (400 MHz, D6-DMS0/CD30D) there is an approximately 3:2 mixture of the pairs of diastereoisomers.
delta = 4.92 ppm (d,~ CH-CH3) delta z 4.98 ppm (d,~ CH-CH3) -. :
ExamPle 4 ~-- .
~-~ N-l2-~4-CarboxymethoxYphenyl)-l-methylethyl]-2-hvaroxy- 2-~6-chloro-pyridin-2-Yl)ethanamine - ; -. ., ~ . ~
~ Palr of di~stereolsomers A~
h''~ g.3 q of a 3:2 ~ixture of the pairs of dlastereoisomers A and B obtained as describea in Example 3 are m~ dis~olvea hot in ~mixturc of 600 ~1 of methanol nd 900 l of water and crystallisea by cooling in an ice b~th. This cry-tallisation prooess 1 - ~ repeated three times wlth 360 ml of meth~nol + -450 Rl of ~ter ~nd 250 ml of methanol ~ 3~0 ml ~-of water. The palr of diastereolsomers A ~re then obtainea in a degree of purity of about 96%. ~ -Ylela: l q (17.2~ of theory), MeItlnq point: 234C
Calculated: C 59.26 H 5.80 N 7.67 Cl 9.71 Found: 59.07 5.69 7.66 9.97 1H-NMR spectrum ~400 MHZ, CD30D/D6-DMS0) delta ~ 4.949 ppm (dd~ CH-OH) ~. .. ~ ~ , ..
133~0~
", Example S
N-12-(4-Carboxymethoxyphenyl~-l-methylethyl~
2-hYdroxy-2-(6-chloro-pyridin-2-Yl)ethanamine-hvdro- '' .. , ', chloride Pair of diastereoisomees B
3.6 9 (0.0095 mol) of a 1:1 mixture of the pairs of diastereoisomers A and B of N-[2-(4-carbomethoxy-methoxyphenyl)-l-methylethyl]-2-hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine obtained as described in Example 1, are stirred in 20 ml of methanol and 50 ml t0.05 mol) of lN sodium hydroxide solution at ambient temperature for 45 minutes. The solution is mixed with 50 ml of lN hydrochloric acid and brought to dryness. The residue is stirred overnight with 20 ml of methanol and 20 ml of water and the solid product precipitated is suction filtered.
The mother liquor is concentrated by evaporation and the residue is triturated with 25 ml of water, then twice with 50 ml and 30 ml, respectively, of acetone and suction filtered. The pair of diastereo- ~- -isomers B is then present in the form of the hydro-chloride with a degree of purity of 90%. - - -Yield: 1 9 (56% of theory), Melting point: about 80C ~decomposition) Calculated: C 53.87 H 5.52 N 6.97 Cl 17.66 Found: 53.82 5.66 6.86 17.50 H-NMR spectrum ~400 MHz, CD3OD/D6-DMSO) delta = 4.907 ppm (dd,> CH-OH) ~ - .
~ ~' - ' .
~ .~
:
,:
.
~ -20- 27169-150 1331~
Example 6 N-[2-(4-(2-Hydroxyethoxy)phenyl-l-methylethyl]-2-hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine Pair of diastereoisomers A:
48.6 g of a 1:1 mixture of the pairs of diastereoisomers of N-[2-(4-(2-Hydroxyethoxy)phenyl)-l-methylethyl~-2-hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine (Example 2) are dissolved in 500 ml of hot acetone and brought to crystallization by cooling in an ice bath, whereby an approximately 8:2 mixture of pairs of diastereoisomers B and A is obtained (yield 15.5 g, melting point:
134C. The volume of mother liquor is reduced to 200 ml and this is cooled overnight in a refrigerator. The product precipitated ~ ~-is suction filtered, dissolved in 150 ml of hot acetone and . . .
crystallized by cooling in an ice bath. This procedure is -: ..., .. ~ .
repeated with 100 ml of acetone and with 70 ml of acetone, yielding -6 g of a product with a melting point of 108C. These 6 g were ~ --~ . . -recrystallized twice more from 60 ml and 40 ml, respectively, of - -acetone, to give the pure pair of diastereoisomers A.
. ~, . .-~:, : .
Yield: 4 g (16.5% of theory), ~-Melting point: 109-110C
Calculated: C 61.62 H 6.60 N 7.98 Cl 10.10 Found: 61.55 6.64 7.86 10.30 - -H-NMR spectrum (400 MHz, CDCl ) delta = 4.620 ppm (dd, ~ CH-OH) Pair of diastereoisomers B:
15.5 g of a mixture of pairs of diastereoisomers N-~2-(4-(2-Hydroxyethoxy)phenyl)-l-methylethyl]-2 hydroxy-2-(6-chloro-.. .:: :.
-20a- 27169-150 ~. ~ 3 1 ~
pyridin-2-yl)ethanamine (Example 2) (B:A = about 8:2) were re-crystallized four times from 600 ml, 500 ml, 400 ml and 350 ml, respectively, of acetone. The pair of diastereoisomers B is obtained with a degree of purity of 96 to 98%. -~
,. i ,.,~ -' ;~
- 13310~
Yield: 7 9 ~56.5~ of theory), Melting point: 142-143C
Calculated: C 61.62 H 7.98 N 7.98 Cl 10.10 Found: 61.45 8.01 7.689.98 ~ -NMR spectrum (400 MHz, CDC13) delta = 4.686 ppm ~dd, CH-0H) Example I
Coated tablet containinq 10 mq of N-12-(4-(2-hYdroxY-ethoxY)Phenvl)-l-methYlethyl]-2-hyaroxy-2-(6-chloro- --Pyridin-2-Yl)ethanamine ComPositiOn 1 coated tablet contains~
(1) Active ~ubstance 10.0 mg (2) Lactose 69.0 mg -~
(3) Corn starch 35.0 mg (4) Polyvinylpyrrolidone5.0 mg -~
also provides a process for the preparation of compounds of the invention, said process comprising at least one of the following steps: -(a) reacting a compound of formula II
:' ', H
Y - N - Y (II) (wherein one of the moieties Y represents a hydrogen - :
atom and the other represents a group of formula ~ ~
~ OH , 3 ~ -Cl N CH-CH2- - CH - CH2 ~ R ~ -~
' -wherein R is as hereinbefore defined~
with a compound of formula III :
':, : - -Zl U (III) (wherein U represents a group of formula , CH
or - , 3 ~
-CH2-CH ~ N ~ Cl -cH-cH2 ~ R
o~r '~ ' ' '' wherein R is as hereinbefore defined, and .: ': ,' ','~, Zl and V together represent a bond, or ;-- 133100$
!
Zl represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a sulphonyloxy group, e.g. a methane-sulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyl-oxy group and V represents a hydrogen atom) (b) reductively aminating a carbonyl compound of formula IV
- ,~
CH3-CO-cH2 ~ R ~
:,~: : : :' Iwherein R i8 a~ hereinbefore defined) ~; with an amine of formula V
. . .~..
ON ~ X , . - :~.~;
Cl N CH-~H2-N
c) reducing a compound of formula VI
ClJ~CO-CN2-N-CX-CXz~R ~ ~
~:: :: :,.; ` . :
.,., . ..,,..,:,,- ~ .-:
= ~:
~ 3 3 1 0 a 3 (wherein R is as hereinbefore defined); -:
(d) reacting a compound of formula VII
-CHrN--CH-CH2~0H
with a compound of formula VIII
:
Z2 ~ Rl (VIII) :, ; ..
(wherein .;: -: Rl represents a carboxymethyl, methoxycarbonyl- ~ :
methyl, ethoxycarbonylmethyl or 2-hydroxy-ethyl -.
group, and Z2 represents a nucleophilic ieaving group such as a halogen atom or a sulphonyloxy group, e.g. ~ :
a chlorine, bromine or iodine atom or a methanesul-phonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy ~" : group, or " , :
Z2 together with a ~-hydrogen atom of the group Rl represents an oxygen atom);
., - ~ ..
e) hydrolysing a resulting compound of formula - ..
I wherein R represents a methoxycarbonylmethoxy or ethoxycarbonylmethoxy group to yield a corresponding . ::
compound of formula I wherein R represents a carboxy- .
methoxy group; : -:
:..: ' ~) converting a compound of formula I into an acid addition salt thereof, or an acid addition ,~,x,., ~,",~" ~
1 3 31 ~ 0 S
salt of a compound of formula I into the free base;
and (g) resolving a resulting compouna of formula I or a salt thereof into its aiastereomers or enant- r iomers.
The reaction of step (a) may conveniently be carried out in a solvent or mixture of solvents such as methanol, ethanol, acetone, diethylether, methyl- - -formamide, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetra~
hyarofuran, dioxan or in an excess of the compound ~ --of formula III used. Optionally the reaction is -~
effected in the presence of an acid binding agent, -e.g. an allcoxide such as potassium tert.butoxide, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as soaium ~-amide, an alkali metal hydride such as ~odium hydride, a tertiary organic base~such as triethylamine, N,N-diisopropylethylamine or pyridine, where the latter may also be s1multaneously used as solvent, or in the presence of a reaction accelerator such potassium iodide. The reaotion is conveniently ` ~ -effected at temperatures between O and 150-C, depending ;~ -on the reactivity of the nucieophilically exchangeable ~`~
group, preferably at a temperature between SO u and 120C, e.g. at the boiling temperature of the solvent u~ied, The reaction may, howëver,~also be carried out without a solvent. It is particularly advantageous to carry out the reaction with a corres~
ponding epoxide of formula III without the addition ; ` ;`
of an acid binding agent. `-'~
The reductive amination of step ~b) may be carried `~
out in a ~olvent such as methanol, ethanol, tetra-? ,`
~331~
hydrofuran, dioxan or acetonitrile in the presence of a reducin~ agent such as a complex metal hydride, but preferably in the presence of sodium cyanoboro-hydride at a p~ of from 5 to 7, and conveniently at temperatures of between 0 and 50C, but preerably at ambient temperature.
The reduction of step (c) may preferably be carried out in a solvent such as methanol, ethanol, diethylether or tetrahydrofuran in the presence of a metal hydride such as sodium borohydride, lithium aluminium hydride, diborane, borane/dimethylsulphide or sodium cyanoboro-hydride, but preferably with sodium borohydride in methanol or ethanol and conveniently at temperatures between 0 and 40C, but preferably at ambient témper-ature. -When the reduction of step ~c) is carried out with a complex metal hydride such as lithium aluminium hyaride, diborane or borane/dimethylsulphiae, a carbonyl function present in the group R may be reducea at the same time to yield a methylene group. ~ -The reaction of step ~d) may conveniently be carried out in a solvent such as diethylether, tetrahydrofuran, dioxan, methanol, ethanol or dimethylformamide ana preferably in the presence of an acid-binaing --~
agent such as soaium hydroxide or potassium tert.but-oxide, but preferably in the presence of potassium carbonate or soaium hydriae or pyridine, whilst an organic base such as pyridine may also be use as solvent, or, in order to prepare 2-hydroxy-ethoxy -~
compounas of formula I, with ethylene oxide. The reaction conveniently is effected at temperatures of between 0 and 100C, preferably at temperatures of between 20 and 80C.
::
1331~0~
In the reactions of steps (aJ to (d) described above, reactive groups may be protected during the reaction with conventional protecting groups which are then split off again by conventional methods after the reaction.
Examples of suitable protective groups for a carboxy group include benzyl, tert.butyl, tetrahydropyranyl, trimethylsilyl, benzyloxymethyl, 2-chloroethyl and methoxymethyl groups and a phenacyl group, e.g. a benzoylmethyl group, suitable protecting ~ --groups for an amino or alkylamino group include ~-acetyl, benzoyl, tert.butoxycarbonyl, benzyloxycar~
bonyl, ethoxycarbonyl and benzyl groups and suitable ~ ~ -protecting groups for a hydroxy group include, for example, trityl, fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzyl groups. --. : ~, : ~,:
~, . .; ....
The optional subsequent splitting off of any protecting group used is preferably carried out by hyarolysis in an aqueous solvent, e.g. in water, isopropanol/
water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as hydrochloric or sulphuric acid or in the presence of an alkali ~ `;
metal base such as sodium hydroxide or potas~ium ;;-~
hydroxide, conveniently at temperatures of between 0 and 100C, preferably at the boiling temperature of the reaction mixture. A benzyl or benzyloxycarbonyl group, however, is preferably removed by hydroqenoly-Si8, e.g. with hydroqen in the presence of-a catalyst such as palladium/charcoal in a solvent such as -;
methanol, ethanol, etbyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, conveniently at temperatures of between 0 and 50C, but preferably at ambient temperature, under a hydrogen pressure of from l to 7 bar, but preferably from 3 to S bar.
',:'-'.,`,'..' :` 133~
The hydrolysis of step (e) is carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, ethanol, ethanol/water, water/iso-propanol or water/dioxan, conveniently at temperatures of between -10C and 120C, e.g. at temperatures of between ambient temperature and the boiling temperature of the reaction mixture.
The compounds of formula I obtained may be converted into the acid addition salts thereof, more particularly for pharmaceutical use the physiologically acceptable salts with inorganic or organic acids. Suitable acids for salt formation include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, fumaric, succinic, lactic, citric, tartaric and maleic acid.
As already mentioned hereinbefore, the compounds of formula I may occur in the form of the enantiomers, enantiomer mixtures or racemates thereof or in the form of pairs of diastereoisomers or mixtures - -of pairs of diastereoisomers.
Thus, the compounds of formula I obtained may be separated into their diastereoisomers on the basis of their physical/chemical differences by methods known Per se, e.g. by chromatography and/or fractional crystallisation. A pair of enantiomers thus obtained - ~-~
may then be separated into the optical antipodes thereof by methods known Per se (see Allinger N.L.
and Eliel E.L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), e.g. by recrystal-lisation from an optically active solvent or by reaction with an optically active substance which ~33~ 00~
g forms salts with the racemic compound, particularly an acid, and separation of the salt mixture obtained ~ -in this way, e.g. on the basis of differences in solubility, into the diastereomeric salts, from which the free antipodes can be liberated by the action of suitable agents. Optically active acids which are particularly useful include the D and ~ - -L forms of tartaric acid, di-o-toluene tartaric acid, malic acid, mandelic acid, camphor sulphonic acid, glutamic acid, aspartic acid and quinic acid.
The compounds used as starting materials which may, obviously, also be used in their optically pure forms, may be obtained by methods known from the literature (see ~Thiazole and its Derivativesn in Heterocyclic Compounds, Vol. 34, and Advances - -~
in Heterocyclic Chemistry, Vol 17, page lOOff (1974)) p~ --or are known from the literature. In some cases these compounds are only present in the reaction mixture and therefore cannot be isolated. ~ ~ ~
An intermediate compound of formula II, V, VI or - -VII may be obtained by corresponding alkylation of a suitable amine, e.g. as discussed in EP-A-239815.
An intermediate compound of formula III wherein Zl represents a nucleophilic leaving group maybe ~ ~-obtained by reduction of a corresponding acetyl compouna, e.g. with a complex metal hydride, or -by conversion of a corresponding hydroxy compound into a reactive derivative tbereof.
''-''''.'- :
An epoxide of an intermediate compound of formula III may be obtained for example by reacting a suitable bromo- or tosylethanol with aqueous potassium or sodium hydroxide ~olution.
' ' ' ~::
', ~
: 133100~
AS already mentioned hereinbefore, the compounds of formula I, the enantiomers, mixtures of enantiomers or racemates thereof or, if they contain at least 2 asym-metric carbon atoms, the diastereoisomers or mixtures of diastereoisomers, and the acid addition salts thereof, more particularly for pharmaceutical use the physiologically acceptable acid addition salts thereof, have valuable pharmacological properties, including, in addition to the effect of inhibiting platelet aggre-gation, an effect on the metabolism, especially an effect of lowering blood sugar and reducing body fat, and the effect of reducing the atherogenic ~-lipopro-teins VLDL and LDL. Moreover, some of the compounds mentioned above also have an anabolic activity.
The biological properties of the new compounds ~ -were investigated as follows:
1. Antidiabetic activitv .
The antidiabetic activity of the compounds according to the invention can be measured as a blood sugar-reducing effect in experimental animals. The test substances were suspended in 1.5% methyl cellulose and aaministered to laboratory-bred fema~e mice by oesophageal tube. 30 minutes later, 1 g of glucose per kg of body weight was dissolved in water and administered subcutaneously. After another 30 minutes, blood was taken from the retroorbital plexus venosus.
The level of glucose in the serum was determined by the hexokinase method using an analytical photometer.
In the Table which follows, the reductions in blood sugar observed in this experimental arrangement are shown as the percentage of a parallel control group.
Statistical evaluation was carried out by the Students t test taking p=0.05 as the limit of significance.
:~ 13310~
Compound ~i Change from the level of (Example No. ) the control group aosage [mg/kg]
O.l 0.3 l.O
l -66 2. Anti-adiPose activitY ~ ~
~ , The anti-adipose activity of the compounas according to the invention was demonstratea by two experimental arrangement a) In the first experiment the increase in lipolysis ~ ~ ~
was measurea by the increase in glycerol in the serum. ~ ~;
The experimental procedure 1s identical to the experi-mental arrangement described above for testing the reauction in blood sugar. The glycerol level was determined in a combined enzymatic/colorimetric test using an analytical photometer. The results are shown in the followlng Table as the percentage of a parallel control group.
Compound~i Change from the level of Example No.) the control group aosage [mg/kg]
, O.l 0.3 l.O
l +882 2 1454 ` ~ -3 +309 878 -~; ~
SA ;
",~
. . , ',' ;'-',..' "; ,,-, ~` 1331~0~
b) In the second experimental arrangement for determining the anti-adipose effect of the compounds according to the invention, the reduction in fatty tissue was measured on the fatty tissue of the ovary by way of example. For this purpose, the compounds were administered to mice once a day by oesophageal tube in a 1.5% methylcellulose suspension. On the fifth day the fatty tissue of the ovary was dissected out and weighed. The following Table shows the results -as a percentage of a parallel control group.
Compound % Change from the level of the con-~Example No.) trol group Dosage: 0.3 [mg/kg]
~ 5~ -54 3. Cardiac side effects The compounds of the invention have been shown to have no undesirable siae effects on the heart in the thera-peutic aosage range which has an effect on the metabo-lism. The evidence for this was provided by the measurement of heart rate in mice during the tests for the blood sugar reducing effect (see above). One hour after oral administration of the compounas heart rate was determined by means of an ECG-triggered tachograph.
The Table which follows shows the change in heart rate -~-as a percentage of the control group.
Compound% Change from the level Dosage ~Example No.) of the control group - ;
3 ~35 10 mg~kg 2 (+6.9) 0.3 mg/kg 27) 0.3 mg/kg .
L;.. ~ ~ - , . . . : : . . : , -: . . ,: . . : .-133~
The figures in brackets are not significant (p greater than 0.05) Furthermore, in the tests on the substances according to the invention described above, no toxic side effects were observed at the dosages used. The substances are therefore well tolerated.
In view of their pharmacological properties, the compounds of formula I and the physiologically --acceptable acid addition salts thereof are therefore suitable for the treatment both of diabetes mellitus and also obesity, particularly for treating obese diabetics. Moreover, the new compounds may be used for the prophylaxis and treatment of athero- -sclerotic changes in the blood vessels, which occur particularly in diabetics and obese people. The -dosage required can be matched entirely to the metabolic physiological requirements of the individual patients since the substances are free from any - -effect on the heart or circulation over a wide -~
aosage range. In adults, therefore, the daily dose may be between l and 3000 mg, but preferably 1 to 1000 mg, divided up into 1 to 4 doses per day. For this purpose, the above-mentioned compounds may be incorporated in conventional galenic prepa- ``
rations such as powders, tablets, coated tablets, capsules, suppositories or suspensions, optionally in conjunction with other active substances.
,:,, , . :Thus, in another aspect, the invention provides - -~
a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable acid ~-addition salt thereof together with at least one ~ -~
pharmaceutical carrier or excipient. It will be understood that the "pharmaceutical compositions~
,.. ::.- . - - . : , , , ~, .. , ,. ,, ,:: :. ., : . . , :,, , ,. ,, ,, . - , . . . .
1 3 ~
of the invention include within their scope compositions suitable -~
for administration to non-human animals, i.e. veterinary composi-tions.
In a still further aspect, the invention provides a method of treatment of the human or non-human body to combat diabetes mellitus, obesity and athero6clerosis comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.
In a yet further aspect, the invention provides the use of a compound of formula I or a physlologically acceptable salt thereof for the preparation of a therapeutic agent for use in the treatment of diabetes mellitus, obesity and atherosclerosis.
In a still further aspect of the invention there is provided a commercial package containing as active pharmaceutical ingredient a compound of formula I or a physiologically acceptable salt thereof, together with instructions for the use thereof in the treatment of diabetes mellitus, obesity and atherosclerosis. -The compounds of the invention may thus also be used to treat overwelght animals such as dogs and, as a consequence of their body fat-reducing (lipolytic) effect, and they may be used to reduce undesirable fat deposits in the fattening of animals, i.e. in order to improve the quality of meat of fattened animals ! . such as pigs, cattle, sheep and poultry. In animals, the above-mentioned compounds may be administered by oral or non-oral routes, e.g. as a feed additive or by injection or by means of ;-implanted minipumps. The daily dose is between 0.01 and 100 mg~kg, preferably between 0.1 and 10 mg/kg of body weight.
B ~ ~-1331~û~
In a still further aspect the invention thus also provides an animal feed comprising a compound of formula I or a -~
physiologically acceptable salt thereof together with a feedstuff.
The Examples which follow are provided to illustrate the ~-~
invention without restricting its scope in any way.
Unless otherwise stated all percentages, parts and ratios referred to herein are by weight.
, ~,. ... ..
-',. -:
,-.~;, . - .
. ,,, ~ , .
. . :.: -- :
~,: . ,,:
.,,.". ;~,:,,, '''"~
-.,- .
: -~ .. , .-.
'.'.'' :".' '.: .,-'' ~ ' ' '., . :- ' : '" ' ' '''.' .: ~' ,~'.
, ,, , " ~:
.~
.:. .~ ,. .:~" ~:
~ " ~ ", 1331~û~
Example 1 N-[ 2-(4-CarbomethoxYmethoxyphenyl)-l-methylethyl]-2-hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine-hYdro-chloride .
0.23 g (0.00133 mol) of 2-hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine and 0.3 9 (0.00133 mol) of 1-(4-carbomethoxymethoxyphenyl)propan-2-one are dissolved in 15 ml of absolute methanol, O.Q8 9 (0.00133 mol) of glacial acetic acid and 0.084 9 (0.00133 mol) of sodium cyanoborohydride are added and the mixture is stirred for 16 hours at ambient temperature.
It is then p~ured onto ice and acidified with hydro-chloric acid. After 5 minutes it is made alkaline with ammonia at 0 to 5C and extracted with methylene chloride. The extract is dried over sodium sulphate and concentrated by evaporation and purified over a silica gel column using ethyl acetate/methanol (9:1) as eluant. The base i8 converted into the hydrochloride using ethereal hydrochloric acid.
Yield: 0.276 9 (46~ of theory), Melting point: from 70C (decomposition).
Calculated: C 54.94 H 5.~2 N 6.74 Cl 17.07 Found: 54.60 6.00 7.00 17.40 According to l~-NMR spectrum (400 MHz, DMSO/CD30D) an approximately 1:1 mixture of the pairs of aiastereo-isomers is present.
delta = 1.17 ppm (d,~ CH-CH3) delt~ - 1.20 pp~ (d,> 0 -~d3) .- :' -~ ~
~,~"~
~3310~
Example 2 ~ -.: .
N-[2-(4-(2-Hydroxyethoxy~phenyl)-l-methylethyl]-2- , ' ~ , hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine-hydro-chloride Prepared analogously to Example 1 by reacting 2- -hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine with - ~ - `
1-(4-(2-hydroxyethoxy)phenyl)propan-2-one and sodium ;
cyanoborohydride and subsequently purifying the -product over a silica gel column using ethyl acetate/- ~ -methanol (9:1) as eluant. The base is converted - --into the hydrochloride using ethereal hydrochloric acid. ;-Yield: 65~ of theory, Melting point: 68C ~decomposition) ~ ~-Calculated: C 55.81 H 6.24 N 7.23 Cl 18.30 Found: 55.60 6.46 7.09 18.47 -~
According to H-NMR spectrum (400 M~z, d6-DMS0/CD30D) -an approximately 1:1 mixture of the pairs of diastereo-isomers i8 present.
delta = 1.121 ppm (d,> CH-CH3) ~-delta = 1.136 ppm (d,~ CH-CH3) -~
ExamPle 3 -~
N-[2-(4-CarboxYmethoxYPheny~ -methylethyll-2 hyaroxy-2-~6-chloro-pvridin-2-Yl)ethanamine ,. . .
3.6 g (0.0095 mol) of N-12-(4-carbomethoxymethoxy-phenyl)-l-methylethyl]-2-hydroxy-2-~6-chloro-pyridin-2-yl)ethanamine are dissolved in 20 ml of methanol and 50 ml tO.05 mol) of lN sodium hydroxide solution are added. The solution iæ stirred for 30 minutes at ambient temperature and then neutralised with 50 ml of lN hydrochloric acid (0.05 mol). The solvent is distilled off in vacuo and the residue - ;
1 3 3 1 0 ~ 5 - 18 - ;
is stirred with 20 ml of water and 20 ml of methanol for 16 hours, suction filtered and washed with a little methanol.
Yield: 1.8 g ~52% of theory), Melting point: 218C ~decomposition).
Calculated: C 59.25 H 5 . 80 N 7.68 Found: 59.47 5.83 7.5s According to 1H-NMR spectrum (400 MHz, D6-DMS0/CD30D) there is an approximately 3:2 mixture of the pairs of diastereoisomers.
delta = 4.92 ppm (d,~ CH-CH3) delta z 4.98 ppm (d,~ CH-CH3) -. :
ExamPle 4 ~-- .
~-~ N-l2-~4-CarboxymethoxYphenyl)-l-methylethyl]-2-hvaroxy- 2-~6-chloro-pyridin-2-Yl)ethanamine - ; -. ., ~ . ~
~ Palr of di~stereolsomers A~
h''~ g.3 q of a 3:2 ~ixture of the pairs of dlastereoisomers A and B obtained as describea in Example 3 are m~ dis~olvea hot in ~mixturc of 600 ~1 of methanol nd 900 l of water and crystallisea by cooling in an ice b~th. This cry-tallisation prooess 1 - ~ repeated three times wlth 360 ml of meth~nol + -450 Rl of ~ter ~nd 250 ml of methanol ~ 3~0 ml ~-of water. The palr of diastereolsomers A ~re then obtainea in a degree of purity of about 96%. ~ -Ylela: l q (17.2~ of theory), MeItlnq point: 234C
Calculated: C 59.26 H 5.80 N 7.67 Cl 9.71 Found: 59.07 5.69 7.66 9.97 1H-NMR spectrum ~400 MHZ, CD30D/D6-DMS0) delta ~ 4.949 ppm (dd~ CH-OH) ~. .. ~ ~ , ..
133~0~
", Example S
N-12-(4-Carboxymethoxyphenyl~-l-methylethyl~
2-hYdroxy-2-(6-chloro-pyridin-2-Yl)ethanamine-hvdro- '' .. , ', chloride Pair of diastereoisomees B
3.6 9 (0.0095 mol) of a 1:1 mixture of the pairs of diastereoisomers A and B of N-[2-(4-carbomethoxy-methoxyphenyl)-l-methylethyl]-2-hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine obtained as described in Example 1, are stirred in 20 ml of methanol and 50 ml t0.05 mol) of lN sodium hydroxide solution at ambient temperature for 45 minutes. The solution is mixed with 50 ml of lN hydrochloric acid and brought to dryness. The residue is stirred overnight with 20 ml of methanol and 20 ml of water and the solid product precipitated is suction filtered.
The mother liquor is concentrated by evaporation and the residue is triturated with 25 ml of water, then twice with 50 ml and 30 ml, respectively, of acetone and suction filtered. The pair of diastereo- ~- -isomers B is then present in the form of the hydro-chloride with a degree of purity of 90%. - - -Yield: 1 9 (56% of theory), Melting point: about 80C ~decomposition) Calculated: C 53.87 H 5.52 N 6.97 Cl 17.66 Found: 53.82 5.66 6.86 17.50 H-NMR spectrum ~400 MHz, CD3OD/D6-DMSO) delta = 4.907 ppm (dd,> CH-OH) ~ - .
~ ~' - ' .
~ .~
:
,:
.
~ -20- 27169-150 1331~
Example 6 N-[2-(4-(2-Hydroxyethoxy)phenyl-l-methylethyl]-2-hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine Pair of diastereoisomers A:
48.6 g of a 1:1 mixture of the pairs of diastereoisomers of N-[2-(4-(2-Hydroxyethoxy)phenyl)-l-methylethyl~-2-hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine (Example 2) are dissolved in 500 ml of hot acetone and brought to crystallization by cooling in an ice bath, whereby an approximately 8:2 mixture of pairs of diastereoisomers B and A is obtained (yield 15.5 g, melting point:
134C. The volume of mother liquor is reduced to 200 ml and this is cooled overnight in a refrigerator. The product precipitated ~ ~-is suction filtered, dissolved in 150 ml of hot acetone and . . .
crystallized by cooling in an ice bath. This procedure is -: ..., .. ~ .
repeated with 100 ml of acetone and with 70 ml of acetone, yielding -6 g of a product with a melting point of 108C. These 6 g were ~ --~ . . -recrystallized twice more from 60 ml and 40 ml, respectively, of - -acetone, to give the pure pair of diastereoisomers A.
. ~, . .-~:, : .
Yield: 4 g (16.5% of theory), ~-Melting point: 109-110C
Calculated: C 61.62 H 6.60 N 7.98 Cl 10.10 Found: 61.55 6.64 7.86 10.30 - -H-NMR spectrum (400 MHz, CDCl ) delta = 4.620 ppm (dd, ~ CH-OH) Pair of diastereoisomers B:
15.5 g of a mixture of pairs of diastereoisomers N-~2-(4-(2-Hydroxyethoxy)phenyl)-l-methylethyl]-2 hydroxy-2-(6-chloro-.. .:: :.
-20a- 27169-150 ~. ~ 3 1 ~
pyridin-2-yl)ethanamine (Example 2) (B:A = about 8:2) were re-crystallized four times from 600 ml, 500 ml, 400 ml and 350 ml, respectively, of acetone. The pair of diastereoisomers B is obtained with a degree of purity of 96 to 98%. -~
,. i ,.,~ -' ;~
- 13310~
Yield: 7 9 ~56.5~ of theory), Melting point: 142-143C
Calculated: C 61.62 H 7.98 N 7.98 Cl 10.10 Found: 61.45 8.01 7.689.98 ~ -NMR spectrum (400 MHz, CDC13) delta = 4.686 ppm ~dd, CH-0H) Example I
Coated tablet containinq 10 mq of N-12-(4-(2-hYdroxY-ethoxY)Phenvl)-l-methYlethyl]-2-hyaroxy-2-(6-chloro- --Pyridin-2-Yl)ethanamine ComPositiOn 1 coated tablet contains~
(1) Active ~ubstance 10.0 mg (2) Lactose 69.0 mg -~
(3) Corn starch 35.0 mg (4) Polyvinylpyrrolidone5.0 mg -~
(5) Magnesium stearate 1.0 mq '20.0 mg PreDaration ;" ~,~ ~:, .'' ',:',, Components (1), (2) and (3) are mixed together ;~
and moistened with component (4) in an aqueous -;~
solution. The moist mass is passed through a screen with a mesh size of 1.6 mm and dried at 45C in a circulating air dryer. The dry granules are passed through a screen with a mesh size of 1 mm -and mixed with component (5). The finished mixture is compressed to form tablet cores. ; `~
~.,-',.'".;'-,'"''`.' Weight of core: 120 mg Diameter: 7.0 mm Radius of curvature: 6.0 mm .`''''' ~
~.':' :' -::- :: .
- :'`"' ~33100~
.
The tablet cores thus produced are coated in known manner with a coating consisting essentially of sugar and talc. This coating may also contain dye extracts. The finished coated tablets are polished with wax.
Weight of coated tablet: 180.0 mg Example II
Coated tablet containinq 50 mq of N-12-(4-(2-hydroxy-ethoxv)Phenyl)-l-methvlethyl~-2-hydroxv-2-(6-chloro-P~Yridin-2-yl)ethanamine comPOSition:
1 coated tablet contains:
'., (1) Active substance 50.0 mg ~ ~-(2) Lactose 110.8 mg (3) Corn starch 50.0 mg (4) Polyvinylpyrrolidone8.0 mg (5) Magnesium stearate 1.2 mq 220.0 mg ., PreParation:
The tablets are prepared analogously to Example I.
Weight of core: 220.0 mg Diameter: 9.0 mm Radius of curvature: 8.0 mm Weight of coated tablet:300.0 mg ~ -Example III
Tablets containinq 150 mq of N-[2-(4-(2-hYdroxYethoxY)-phenYl)-l-methylethYl]-2-hYdroxY-2-(6-chloro-pyridin 2-yl)ethanamine -` 1331~
Composition~
1 tablet contains:
(1) Active substance 150.0 mg ~2~ Lactose 86.0 mg (3) Corn starch 50.8 mg (4) Microcrystalline cellulose2S.0 mg (5) Polyvinylpyrrolidone 7.0 mg (6) Magnesium stearate 1.2 mq 320.0 mg . ,~
PreParation- ' ''' ~
- : -. :-Components (1), (21, (3), (4) and (S) are mixea ;~
together and moistened with water. The moist mass is passed through a screen with a mesh size of 1.6 mm and dried at 45C. The dried granules are ;- ;~
passed through the same screen again and mixed with component (6). Tablets are compressed from the finished mixture. - -., Weight of tablet: 320.0 mg ~-Diameter: 10.0 mm , ~ ,-.. ,-, The tablets are provided with a divlding notch -to make it easier to break them in half.
ExamPle IV "",~
Hard aelatin caPsules containinq 100 mq of N-[2-4-(2-hYdroxyethyl)phenyl)-l-methylethyl]-2-hydroxv- '~
2-~6-chloro-PYridin-2-yl)ethanamine ComPosition 1 capsule comprises~
. ' '~'~','~` .
Capsule casing: hard gelatin capsules, size 3 ~ ~
,.- ~. .,~, ..
",.:,.
~ ~3310~5 Capsule contents:
(1) Active substance 100.0 mg (2) Lactose x lH2o 38.0 mg (3) Dried corn starch 60.0 mg (4) Magnesium stearate 2.0 mq Weight of capsule filling: 200.0 mg (5) Distilled water q.s.
PreParation:
A small amount of lactose is dissolved to about 10% in distillea water ~granulating liquid~. The active substance, the remaining lactose and corn starch are mixed together and moistened with the granulating liquid. The mass is screened, dried, re-screened and homogeneously mixed with magnesium stearate. The fine granules are packed into capsules in a suitable machine.
ExamPle V
Hard qelatin caPsules containinq 200 mq of N-[2-(4-~2-hYdroxYethoxY)Phenyl)-l-methylethvl]-2-hydr 2-~6-chloro-pYridin-2-Yl)ethanamine '~1`, ,. ~ .
ComPosition~
~. . ..
Capsule casing: hard gelatin capsules, size 1 Capsule contents:
i ' ' ! ~ 1) Active substance200.0 mg ~2) Lactose x lH2O 47.0 mg ~3) Dried corn starch70.0 mg ~4) Magnesium stearate3.0 mq Weight of capsule filling: 320.0 mg (5) Di~tilled water q.s.
:" ' t331~0~ j . ., :
PreParation: ;
A small amount of lactose is dissolved, to about -10% in distilled water ~granulating liquid!. The active substance, the remaining lactose and corn ~ ~ .
starch are mixed together and moistened with the granulating liquid. The mass is screened, dried, re-screened and homogeneously mixed with magnesium stearate. The fine granules are packed into capsules in a suitable machine.
-., ~
1 ~ ' ~ ' ' " " ~,: ,' ` . ';
'''`~ ' .
':
~, '`'., "' '"'': ~,~
,: ~ ,.,.. :, .'..: '' ~ -:
; -: . '':, .-: '-' ~` ~ ' , .
and moistened with component (4) in an aqueous -;~
solution. The moist mass is passed through a screen with a mesh size of 1.6 mm and dried at 45C in a circulating air dryer. The dry granules are passed through a screen with a mesh size of 1 mm -and mixed with component (5). The finished mixture is compressed to form tablet cores. ; `~
~.,-',.'".;'-,'"''`.' Weight of core: 120 mg Diameter: 7.0 mm Radius of curvature: 6.0 mm .`''''' ~
~.':' :' -::- :: .
- :'`"' ~33100~
.
The tablet cores thus produced are coated in known manner with a coating consisting essentially of sugar and talc. This coating may also contain dye extracts. The finished coated tablets are polished with wax.
Weight of coated tablet: 180.0 mg Example II
Coated tablet containinq 50 mq of N-12-(4-(2-hydroxy-ethoxv)Phenyl)-l-methvlethyl~-2-hydroxv-2-(6-chloro-P~Yridin-2-yl)ethanamine comPOSition:
1 coated tablet contains:
'., (1) Active substance 50.0 mg ~ ~-(2) Lactose 110.8 mg (3) Corn starch 50.0 mg (4) Polyvinylpyrrolidone8.0 mg (5) Magnesium stearate 1.2 mq 220.0 mg ., PreParation:
The tablets are prepared analogously to Example I.
Weight of core: 220.0 mg Diameter: 9.0 mm Radius of curvature: 8.0 mm Weight of coated tablet:300.0 mg ~ -Example III
Tablets containinq 150 mq of N-[2-(4-(2-hYdroxYethoxY)-phenYl)-l-methylethYl]-2-hYdroxY-2-(6-chloro-pyridin 2-yl)ethanamine -` 1331~
Composition~
1 tablet contains:
(1) Active substance 150.0 mg ~2~ Lactose 86.0 mg (3) Corn starch 50.8 mg (4) Microcrystalline cellulose2S.0 mg (5) Polyvinylpyrrolidone 7.0 mg (6) Magnesium stearate 1.2 mq 320.0 mg . ,~
PreParation- ' ''' ~
- : -. :-Components (1), (21, (3), (4) and (S) are mixea ;~
together and moistened with water. The moist mass is passed through a screen with a mesh size of 1.6 mm and dried at 45C. The dried granules are ;- ;~
passed through the same screen again and mixed with component (6). Tablets are compressed from the finished mixture. - -., Weight of tablet: 320.0 mg ~-Diameter: 10.0 mm , ~ ,-.. ,-, The tablets are provided with a divlding notch -to make it easier to break them in half.
ExamPle IV "",~
Hard aelatin caPsules containinq 100 mq of N-[2-4-(2-hYdroxyethyl)phenyl)-l-methylethyl]-2-hydroxv- '~
2-~6-chloro-PYridin-2-yl)ethanamine ComPosition 1 capsule comprises~
. ' '~'~','~` .
Capsule casing: hard gelatin capsules, size 3 ~ ~
,.- ~. .,~, ..
",.:,.
~ ~3310~5 Capsule contents:
(1) Active substance 100.0 mg (2) Lactose x lH2o 38.0 mg (3) Dried corn starch 60.0 mg (4) Magnesium stearate 2.0 mq Weight of capsule filling: 200.0 mg (5) Distilled water q.s.
PreParation:
A small amount of lactose is dissolved to about 10% in distillea water ~granulating liquid~. The active substance, the remaining lactose and corn starch are mixed together and moistened with the granulating liquid. The mass is screened, dried, re-screened and homogeneously mixed with magnesium stearate. The fine granules are packed into capsules in a suitable machine.
ExamPle V
Hard qelatin caPsules containinq 200 mq of N-[2-(4-~2-hYdroxYethoxY)Phenyl)-l-methylethvl]-2-hydr 2-~6-chloro-pYridin-2-Yl)ethanamine '~1`, ,. ~ .
ComPosition~
~. . ..
Capsule casing: hard gelatin capsules, size 1 Capsule contents:
i ' ' ! ~ 1) Active substance200.0 mg ~2) Lactose x lH2O 47.0 mg ~3) Dried corn starch70.0 mg ~4) Magnesium stearate3.0 mq Weight of capsule filling: 320.0 mg (5) Di~tilled water q.s.
:" ' t331~0~ j . ., :
PreParation: ;
A small amount of lactose is dissolved, to about -10% in distilled water ~granulating liquid!. The active substance, the remaining lactose and corn ~ ~ .
starch are mixed together and moistened with the granulating liquid. The mass is screened, dried, re-screened and homogeneously mixed with magnesium stearate. The fine granules are packed into capsules in a suitable machine.
-., ~
1 ~ ' ~ ' ' " " ~,: ,' ` . ';
'''`~ ' .
':
~, '`'., "' '"'': ~,~
,: ~ ,.,.. :, .'..: '' ~ -:
; -: . '':, .-: '-' ~` ~ ' , .
Claims (9)
1. Compounds of formula I
(I) (wherein R represents a carboxymethoxy, carbomethoxymethoxy, ethoxycarbonylmethoxy or 2-hydroxyethoxy group) and the optical isomers, diastereoisomers and acid addition salts thereof.
(I) (wherein R represents a carboxymethoxy, carbomethoxymethoxy, ethoxycarbonylmethoxy or 2-hydroxyethoxy group) and the optical isomers, diastereoisomers and acid addition salts thereof.
2. A compound as claimed in claim 1 being N-[2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine, or an optical isomer, diastereoisomer or acid addition salt thereof.
3. A compound as claimed in claim 1 or claim 2 being a physiologically acceptable acid addition salt of a compound of formula I.
4. A Pharmaceutical composition for treatment of the human or non-human animal body to combat diabetes, mellitus, obesity or atherosclerosis comprising a pharmaceutically effective amount of a compound of formula I as claimed in claim 1 or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient.
5. A process for the preparation of compounds as claimed in claim 1, said process comprising at least one of the following steps:
a) reacting a compound of formula II
(II) (wherein one of the moieties Y represents a hydrogen atom and the other represents a group of formula or wherein R is as defined in claim 1) with a compound of formula III
Z1-U (III) (wherein U represents a group of formula or wherein R is as defined in claim 1; and Z1 and V together form a bond, or Z1 represents a nucleophilic leaving group and V represents a hydrogen atom) optionally with reactive groups being protected during the reaction by a protecting group and with any said protecting groups being removed thereafter;
b) reductively aminating a carbonyl compound of formula IV
(IV) (wherein R is defined as in claim 1) with an amine of formula V
(V) optionally with reactive groups being protected during the reaction by a protecting group and with any said protecting groups being removed thereafter;
c) reducing a compound of formula VI
(VI) (wherein R is as defined in claim 1) optionally with reactive groups being protected during the reaction by a protecting group and with any said protecting groups being removed thereafter;
d) reacting a compound of formula VII
(VII) with a compound of formula VIII
Z2 - R1 (VIII) (wherein R1 represents a carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl or 2-hydroxyethyl group, and Z2 represents a nucleophilic leaving group or Z2 together with a beta-hydrogen atom of the group R1 represents an oxygen atom), optionally with reactive groups being protected during the reaction by a protecting group and with any said protecting groups being removed thereafter;
(e) hydrolysing a resulting compound of formula I wherein R represents a methoxycarbonylmethyl or ethoxycarbonylmethoxy group to yield a corresponding compound of formula I wherein R represents a carboxy-methoxy group;
(f) converting a compound of formula I into an acid addition salt thereof, or an acid addition salt of a compound of formula I into the free base; and (g) resolving a resulting compound of formula I or a salt thereof into its diastereomers or enantiomers.
a) reacting a compound of formula II
(II) (wherein one of the moieties Y represents a hydrogen atom and the other represents a group of formula or wherein R is as defined in claim 1) with a compound of formula III
Z1-U (III) (wherein U represents a group of formula or wherein R is as defined in claim 1; and Z1 and V together form a bond, or Z1 represents a nucleophilic leaving group and V represents a hydrogen atom) optionally with reactive groups being protected during the reaction by a protecting group and with any said protecting groups being removed thereafter;
b) reductively aminating a carbonyl compound of formula IV
(IV) (wherein R is defined as in claim 1) with an amine of formula V
(V) optionally with reactive groups being protected during the reaction by a protecting group and with any said protecting groups being removed thereafter;
c) reducing a compound of formula VI
(VI) (wherein R is as defined in claim 1) optionally with reactive groups being protected during the reaction by a protecting group and with any said protecting groups being removed thereafter;
d) reacting a compound of formula VII
(VII) with a compound of formula VIII
Z2 - R1 (VIII) (wherein R1 represents a carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl or 2-hydroxyethyl group, and Z2 represents a nucleophilic leaving group or Z2 together with a beta-hydrogen atom of the group R1 represents an oxygen atom), optionally with reactive groups being protected during the reaction by a protecting group and with any said protecting groups being removed thereafter;
(e) hydrolysing a resulting compound of formula I wherein R represents a methoxycarbonylmethyl or ethoxycarbonylmethoxy group to yield a corresponding compound of formula I wherein R represents a carboxy-methoxy group;
(f) converting a compound of formula I into an acid addition salt thereof, or an acid addition salt of a compound of formula I into the free base; and (g) resolving a resulting compound of formula I or a salt thereof into its diastereomers or enantiomers.
6. An animal feed comprising a compound of formula I as claimed in claim 1 or 2 or a physiologically acceptable salt thereof together with a feedstuff.
7. The use of a compound of formula I as claimed in claim 1 or 2 or a physiologically acceptable salt thereof for treatment of the human or non-human body to combat diabetes mellitus, obesity and atherosclerosis.
8. A process for the preparation of a therapeutic agent for use in the treatment of diabetes mellitus, obesity and atherosclerosis, which process comprises admixing a compound of formula I as claimed in claim 1 or 2 or a physiologically acceptable salt thereof with a suitable diluent or carrier.
9. A commercial package containing as active pharmaceutical ingredient a compound of formula I as claimed in claim 1 or 2, or a physiologically acceptable salt thereof, together with instructions for the use thereof in the treatment of diabetes mellitus, obesity and atherosclerosis.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3729284.6 | 1987-09-02 | ||
| DE19873729284 DE3729284A1 (en) | 1987-09-02 | 1987-09-02 | NEW HETEROARYLETHANOLAMINES, MEDICAMENTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1331005C true CA1331005C (en) | 1994-07-26 |
Family
ID=6335037
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000576154A Expired - Fee Related CA1331005C (en) | 1987-09-02 | 1988-08-31 | Pyridylethanolamines, pharmaceutical compositions containing them and processes for their preparation |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0305845B1 (en) |
| JP (1) | JPH0196172A (en) |
| KR (1) | KR890005056A (en) |
| AT (1) | ATE81851T1 (en) |
| AU (1) | AU617353B2 (en) |
| CA (1) | CA1331005C (en) |
| DE (2) | DE3729284A1 (en) |
| DK (1) | DK486988A (en) |
| FI (1) | FI884003A (en) |
| IL (1) | IL87620A0 (en) |
| NZ (1) | NZ226006A (en) |
| PT (1) | PT88392B (en) |
| ZA (1) | ZA886501B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4918086A (en) * | 1987-08-07 | 1990-04-17 | Ciba-Geigy Corporation | 1-nitro-2,2-diaminoethylene derivatives |
| DE4006794A1 (en) * | 1990-03-03 | 1991-09-05 | Bayer Ag | METHOD FOR PRODUCING AMINOETHANOL DERIVATIVES |
| AU2003248614B2 (en) * | 2002-07-17 | 2007-08-30 | Lek Pharmaceuticals D.D. | Novel derivatives of pyridylethanol (phenylethyl) amines as inhibitors of cholesterol biosynthesis, processes for their preparation, and pharmaceutical compositions containing them |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3615293A1 (en) * | 1986-05-06 | 1987-11-12 | Bayer Ag | USE OF HETEROARYLETHYLAMINE FOR PERFORMANCE IN ANIMALS, HETEROARYLETHYLAMINE AND METHOD FOR THE PRODUCTION THEREOF |
| CA1287061C (en) * | 1986-06-27 | 1991-07-30 | Roche Holding Ltd. | Pyridine ethanolamine derivatives |
| DE3627663A1 (en) * | 1986-08-14 | 1988-03-03 | Bayer Ag | HETEROARYLETHYLAMINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A PERFORMANCE IN ANIMALS |
| DE3861031D1 (en) * | 1987-03-07 | 1990-12-20 | Bayer Ag | METHOD FOR PRODUCING 5-AMINO-4,6-DIHALOGENPYRIDINE. |
-
1987
- 1987-09-02 DE DE19873729284 patent/DE3729284A1/en not_active Withdrawn
-
1988
- 1988-08-22 AT AT88113612T patent/ATE81851T1/en not_active IP Right Cessation
- 1988-08-22 DE DE8888113612T patent/DE3875563D1/en not_active Expired - Fee Related
- 1988-08-22 EP EP88113612A patent/EP0305845B1/en not_active Expired - Lifetime
- 1988-08-31 CA CA000576154A patent/CA1331005C/en not_active Expired - Fee Related
- 1988-08-31 IL IL87620A patent/IL87620A0/en unknown
- 1988-08-31 FI FI884003A patent/FI884003A/en not_active Application Discontinuation
- 1988-08-31 NZ NZ226006A patent/NZ226006A/en unknown
- 1988-09-01 PT PT88392A patent/PT88392B/en not_active IP Right Cessation
- 1988-09-01 JP JP63219623A patent/JPH0196172A/en active Pending
- 1988-09-01 DK DK486988A patent/DK486988A/en not_active Application Discontinuation
- 1988-09-01 AU AU21790/88A patent/AU617353B2/en not_active Ceased
- 1988-09-01 ZA ZA1988/06501A patent/ZA886501B/en unknown
- 1988-09-01 KR KR1019880011275A patent/KR890005056A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| PT88392B (en) | 1992-10-30 |
| ZA886501B (en) | 2008-05-30 |
| PT88392A (en) | 1989-07-31 |
| DK486988D0 (en) | 1988-09-01 |
| KR890005056A (en) | 1989-05-11 |
| EP0305845A1 (en) | 1989-03-08 |
| DK486988A (en) | 1989-03-03 |
| IL87620A0 (en) | 1989-01-31 |
| DE3875563D1 (en) | 1992-12-03 |
| JPH0196172A (en) | 1989-04-14 |
| FI884003A0 (en) | 1988-08-31 |
| NZ226006A (en) | 1991-05-28 |
| FI884003A (en) | 1989-03-03 |
| AU2179088A (en) | 1989-03-02 |
| EP0305845B1 (en) | 1992-10-28 |
| DE3729284A1 (en) | 1989-03-23 |
| AU617353B2 (en) | 1991-11-28 |
| ATE81851T1 (en) | 1992-11-15 |
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| MKLA | Lapsed |