AP301A - "4-(2-(2-Hydroxy-2-phenylethylamino) ethoxy)phenylacetic acid,derivatives for use in the treatment of obesity and related conditions. - Google Patents

"4-(2-(2-Hydroxy-2-phenylethylamino) ethoxy)phenylacetic acid,derivatives for use in the treatment of obesity and related conditions. Download PDF

Info

Publication number
AP301A
AP301A APAP/P/1992/000385A AP9200385A AP301A AP 301 A AP301 A AP 301A AP 9200385 A AP9200385 A AP 9200385A AP 301 A AP301 A AP 301A
Authority
AP
ARIPO
Prior art keywords
compound
formula
hydroxy
phenylethylamino
cor
Prior art date
Application number
APAP/P/1992/000385A
Other versions
AP9200385A0 (en
Inventor
Brian Roy Holloway
Ralph Howe
Balbir Singh Rao
Original Assignee
Zeneca Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zeneca Ltd filed Critical Zeneca Ltd
Publication of AP9200385A0 publication Critical patent/AP9200385A0/en
Application granted granted Critical
Publication of AP301A publication Critical patent/AP301A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/04—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/06—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
    • C07C251/08—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton being acyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/22—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/04—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/10—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C251/16—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms

Abstract

Compounds of the formula

Description

CHEMICAL COMPOUNDS •
The present invention relates to 4-[2-(2-hydroxy-2-phenylethylamino)ethoxyIphenylacetic acid and bioprecursors thereof. This invention further relates to processes and intermediates for their preparation, to their use in methods of therapy and to pharmaceutical compositions containing them. The compounds of the present invention are (^-adrenoceptor agonists and are of value in disease conditions mediated through such adrenoceptors. Administration of the compounds of this invention to varm-blooded animals provides a thermogenic effect, that is thermogenesis is stimulated and administration of the compounds is of use, for example, in the treatment of obesity and related conditions such as mature onset diabetes associated vith obesity. In addition, the compounds of this invention improve glucose tolerance in varm-blooded animals and are of use in combatting disease conditions vherein such activity is beneficial for example they have hypoglycaemic activity. The compounds of this invention may also be used in the treatment of non-insulin dependent diabetes mellitus (NIDDM) and in conditions vherein insulin resistance is of importance such as hypertension, hyperlipidaemia and decreased fibrinolysis (Reaven's syndrome or Syndrome X).
The present applicants have conducted substantial research into ^-adrenoceptor agonists and, in particular into their thermogenic effect. Our ovn United States Patent 4772631 discloses compounds of the formula (A):
OCH2Z (A)
APO 00 3 0 1
- 2 gl bo vherein R is hydrogen or fluoro; R and R are independently selected from hydrogen and C. - alkyl; and 2 is hydroxymethyl or a group of the j a formula -COR in which R is hydroxy, ^alkoxy or amino.
Our own United States Patent the formula (B):
4940168 discloses compounds of
& e f wherein R is hydrogen or fluoro and R and R are independently hydrogen or a variety of groups leading to secondary and tertiary amides. It is believed that compounds of the formula (A) vherein is alkoxy or amino, and the compounds of the formula (B), are primarily bioprecursors that are effective via the corresponding oxyacetic acid; that is the compound of the formula (A) vherein R^ is hydroxy.
The present applicants identified the compound of the formula (A) vherein Ra-Rc vere hydrogen and R^ was hydroxy as being of significant interest. Hovever, this compound did not have an ideal profile of solubility and absorption characteristics. Accordingly, the present applicants developed a secondary amide bioprecursor of this compound. This secondary amide was introduced into human volunteer patients. Disappointingly, there was insufficient effect on metabolic rate in the clinic and this, in effect, pointed to insufficient efficacy of the free carboxylic acid at the 6j-adrenoceptor.
Further investigations vere performed and ve have now discovered a compound which, surprisingly, provides significant thermogenic effects at doses vhich cause relatively few side-effects.
» X
AP000 30 1
- 3 It is understood that selectivity of theraogenic effect, for example lack of cardiac side-effects, is an important requireaent for a useful therapeutic agent in the treataent of, for exaaple, obesity and related conditions.
This conpound of the present invention is a carboxylic acid and shovs significant advantage over the above referred to secondary χ aside and free carboxylic acid. In particular, it has been shovn to have full efficacy at ^-adrenoceptors, vhereas the compound vhich had been administered to man vas found to have lov efficacy. In addition, it has been shovn to have surprisingly good solubility and absorption characteristics.
Accordingly the present invention provides a compound of the formula (I):
ch(oh)ch2nhch2ch2o
ch2cooh (I) or a bioprecursor or a pharmaceutically acceptable salt thereof.
Favourably the compounds of the formula (I) are in the form « of a carboxylic acid or a pharmaceutically acceptable salt thereof.
4-[2-(2-Hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid and certain bioprecursors are amphoteric and may be used in the zvitterionic form, or as a pharmaceutically acceptable acid addition salt, or as a salt vith a base affording a pharmaceutically acceptable cation. Particular examples of pharmaceutically acceptable acid-addition salts include, for example, salts vith inorganic acids such as hydrohalides (especially hydrochlorides or hydrobromides), sulphates and phosphates, and salts vith organic acids such as succinates, citrates, lactates, tartrates and salts derived from acidic vater-soluble polymers. Particular examples of salts vith bases affording a pharmaceutically
- 4 acceptable cation include, for exaaple, alkali metal and alkaline earth metal salts, such as sodium, potassium, calciua and magnesium salts, and ammonium salts and salts vith suitable organic bases such as triethanolamine.
Bioprecursors are those pharmaceutically acceptable compounds that are degraded in the animal body to produce the parent acid. Such compounds can be identified by administering, for example orally to a test animal, the compound under test and subsequently examining the test animal's body fluids.
One class of bioprecursor is that of the corresponding ester bioprecursors of the carboxy group of 4-[2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetic acid. Suitable esters include ^alkyl esters, for example the methyl and ethyl esters.
Another class of bioprecursor is that of the corresponding ester bioprecursors of the hydroxy group (-CH(OH)-). Such esters include, as their acyl group for example, acetyl, propionyl, pivaloyl, Cj ^alkoxycarbonyl for example ethoxycarbonyl and phenylacetyl.
A further class of bioprecursor is that of the corresponding amide bioprecursors of the carboxy group of 4-(2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetic acid. Suitable amides include, for 12 12 example, amides of the formula -CONR R , wherein R and R are independently hydrogen, Cj^alkyl, hydroxyCj^alkyl (wherein the hydroxy substituent is on other than the »-carbon), C^^alkoxyCj ,alkyl, phenylalkyl, allyl, cyclopropyl or cyclopentyl or the group
-NR R^ is morpholino, piperidino or pyrrolidino. In general amides,
2 in particular wherein R and R are independently hydrogen, are primarily viewed as intermediates for the preparation of the corresponding carboxylic acid or ester.
APO 00 3 0 1
- 5 A preferred class of bioprecursors is that of the formula (II):
ch(oh)ch2nhch2ch2o
ch2cor· (II) wherein R is ^alkoxy for exaaple methoxy.
Bioprecursors of 4-(2-(2-hydroxy-2-phenylethylamino)ethoxy(phenylacetic acid may have a thermogenic effect in their own right and this is another aspect of the invention.
Especially preferred compounds of the invention are:
(R)-4-(2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid;
(R)-4-(2-(2-hydroxy-2-phenylethylamino)ethoxy(phenylacetamide; (R)-methyl 4-(2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetate; 4-[2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetic acid;
4-(2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetamide; and methyl 4-[2-(2-hydroxy-2-phenylethylamino)ethoxy(phenylacetate; and pharmaceutically acceptable salts thereof.
It will be appreciated that 4-(2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetic acid and bioprecursors thereof contain one or more asymmetric carbon atoms and can exist as optically active enantiomers or as optically inactive racemates. The present invention encompasses any enantiomer, racemate and/or (when two or more asymmetric carbon atoms are present) diastereoisomer, which when administered in a therapeutic amount provides a thermogenic effect in warm-blooded animals, it being well known in the chemical art how to prepare individual enantiomers, for example by resolution of the racemate or by stereospecific synthesis, and how to determine the ϊο ε ο ο ο ha
- 6 thermogenic properties, for example, using the standard tests described hereinafter. It is preferred that the compounds of the present invention are provided in the (R) absolute configuration at the -CH(OH)- group (under the Cahn-Prelog-Ingold rules).
In order to use a compound of the present invention or a pharmaceutically acceptable salt thereof for the therapeutic treatment of varm-blooded mammals including humans, it is normally formulated in accordance vith standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises 4-(2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid, or a bioprecursor thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for example by oral or parenteral administration. For these purposes they may be formulated by means known to the art into the form of, for example, tablets, capsules, pills, powders, aqueous or oily solutions or suspensions, emulsions, and sterile injectable aqueous or oily solutions or suspensions.
In general compositions for oral administration are preferred.
The compositions may be obtained using standard excipients and procedures well known in the art. A unit dose form such as a tablet or capsule vill usually contain, for example 0.1-500 mg of active ingredient, more suitably 10-250mg, and preferably 50-100mg of the compound of this invention.
The compositions may also contain other active ingredients known for use in the disease condition to be treated, for example appetite suppressants, vitamins, antihypertensives and hypoglycaemic
AP 0 00 30 1
- 7 agents such as sulphonylureas, biguanides and thiazolidinediones. It is understood that such compositions-cover co-formulation, concurrent and sequential therapy of the tvo or more active ingredients.
In one aspect of the present invention, 4-[2-(2-hydroxyi
2-phenylethylamino)ethoxyJphenylacetic acid or a bioprecursor thereof may be formulated for oral administration in a sustained (or delayed) x
release composition, for example a matrix tablet formulation comprising insoluble or svellable polymeric filler, or a coated spheroid formulation.
Vhen used, to produce thermogenic effects in varm-blooded animals including man, 4-(2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetic acid or a bioprecursor thereof or a pharmaceutically acceptable salt thereof as appropriate, vill be administered so that a dose in the general range 0.002-20 mg/kg, suitably in the range 0.02-10 mg/kg, and preferably in the range 0.5-5 mg/kg is administered daily, given in a single dose or divided doses as necessary, typically one to three times a day. Bovever, it vill be appreciated by those skilled in the art that dosage vill necessarily be varied as appropriate, depending on the severity of the condition under treatment and on the age and sex of the patient and according to knovn medical principles.
In addition the compounds of the present invention lover triglyceride levels and cholesterol levels and raise high density ε:
lipoprotein (BDL) levels and are therefore of use in combatting medical conditions vherein such lovering (and raising) is thought to be beneficial. Thus they may be used in the treatment of hypertriglyceridaemia, hypercholesterolaemia and conditions of lov HDL levels in addition to the treatment of atherosclerotic disease such as of coronary, cerebrovascular and peripheral arteries, cardiovascular disease and related conditions.
Accordingly in another aspect the present invention provides a method of lovering triglyceride and/or cholesterol levels and/or increasing HDL levels vhich comprises administering, to an animal in
- 8 need thereof, a therapeutically effective amount of
4-l2-(2-hydroxy-2-phenylethylamindDethoxy]phenylacetic acid or a bioprecursor thereof or pharmaceutically acceptable salt thereof. In a further aspect the present invention provides a method of treating atherosclerosis vhich comprises administering, to an animal in need thereof, a therapeutically effective amount of
4-(2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetic acid or a bioprecursor thereof or pharmaceutically acceptable salt thereof. The compositions are formulated and administered in the same general manner as detailed above for producing a thermogenic'effect. They may also contain other active ingredients known for use in the treatment of atherosclerosis and related conditions, for example fibrates such as clofibrate, bezafibrate and gemfibrozil; inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors for example lovastatin, simvastatin and pravastatin; inhibitors of cholesterol absorption for example beta-sitosterol and (acyl CoA:cholesterol acyltransferase) inhibitors for example melinamide; anion exchange resins for example cholestyramine, colestipol or a dialkylaminoalkyl derivative of a cross-linked dextran; nicotinyl alcohol, nicotinic acid or a salt thereof; vitamin E; and thyromimetics.
In a further aspect the compounds of the present invention stimulate the atypical 0-adrenoceptors in the gastrointestinal tract and therefore inhibit gastrointestinal motility. They may be of use in combatting medical conditions wherein stimulation of atypical (3-adrenoceptors in the gastrointestinal tract is thought to be beneficial, such as in combatting medical conditions wherein inhibition of gastrointestinal motility is thought to be of value. Thus they may be of use for example in the treatment of inflammatory bowel disease (IBD) (such as Crohn's disease and ulcerative colitis), irritable bowel syndrome (IBS), non-specific diarrhoea and dumping syndrome.
Accordingly the present invention provides a method of stimulating the atypical 0-adrenoceptors in the gastrointestinal
AP Ο 00 3 Ο 1
- 9 tract vhich comprises administering, to an animal in need thereof, a therapeutically effective amount o*f a compound of the present invention.
In a further aspect the present invention provides methods of inhibiting gastrointestinal motility, treating IBD, treating IBS, treating non-specific diarrhoea and treating gastric emptying in dumping syndrome vhich comprise administering to an animal in need thereof, a therapeutically effective amount of a compound of the present invention.
In a further aspect the present invention provides a process for preparing 4-(2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid or a bioprecursor thereof or a pharmaceutically acceptable salt thereof vhich process comprises:
a) reacting a compound (III) or (IV) vith a compound of the formula (V):
nh2ch2ch2o
ch2cor4 (HI) (IV) (V)
- ίο vherein -COR is carboxy or its bioprecursor and L is a displaceable group; or
b) hydrolysis of a compound of the formula (VI):
(VI) wherein COR is as hereinbefore defined; or
c) for 4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid hydrolysing a compound of the formula (VII):
ch(oh)ch2nhch2ch2o
ch2cor· (VII) vherein is a hydrolysable group;
d) reacting a compound of the formula (VIII) vith a compound of the formula (IX):
CH(OH)CH2NH2 (VIII)
L'CH2CH2o-r< A-ch2cor4
(IX) ► < AP Ο 00 30 1
- 11 4 vherein -COR is as hereinbefore defined and L' is a displaceable group;
e) deprotecting a coapound of the formula (X):
(X)
4 vherein R is a protected derivative of a group -COR ;
f) converting 4-(2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetic acid into a bioprecursor, or vice versa, or converting a bioprecursor of 4-(2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylaceti acid into another bioprecursor of 4-(2-(2-hydroxy-2-phenylethylamino) ethoxy]phenylacetic acid;
g) reducing a compound of the formula (XI):
coch2nhch2ch2o
ch2cor (XI) vherein -COR is as hereinbefore defined;
h) reducing a compound of the formula (XII) vherein -COR is as hereinbefore defined;
(XII) r ο ε ο ο ο A A
- 12 i) reducing a compound of the formula (XIII):
-CH(OH)CH2N«CHCH2O
ch2cor4 (XIII) vherein COR is as hereinbefore defined;
and vherein any functional group is optionally protected and thereafter if necessary;
(i) removing any protecting groups;
(ii) forming a pharmaceutically acceptable salt.
Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods.
Protecting groups may be removed by any convenient method as described in the literature or knovn to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group vith minimum disturbance of groups elsevhere in the molecule.
A particular protecting group is a hydrogenolysable group present on the nitrogen atom of -CH(OH)CH2NCR2CH2O-. Suitably the protecting group is benzyl or a substituted benzyl group. Such a protecting group may be removed in conventional manner using methods of catalytic hydrogenation, for example palladium on carbon catalysts in an atmosphere of hydrogen. Suitable conditions include ambient and elevated temperatures and pressures in a solvent such as a C2 alkanol for example ethanol or propan-2-ol. Compounds corresponding to formula (I) protected vith a hydrogenolysable group on the nitrogen
AP000301
- 13 atom may be prepared by methods analogous to those described above for formula (I).
The reaction betveen a compound of the formulae (III) or (IV) and a compound of the formula (V) may be performed in a suitable solvent for example an alcohol such as ethanol or propan-2-ol, at a temperature in the range for example 10°C to llO'C and most at conveniently at or near the boiling-point of the reaction mixture. In the compound of the formula (IV) L may be, for example, halogen such as chloro or bromo or an arylsulphonyloxy group such as * ** toluenesulphonyloxy or an alkanesulphonyloxy group such as methanesulphonyloxy.
The compounds of the formula (V) are prepared in any convenient manner known to those skilled in the art. For example they may be conveniently prepared by reacting compound (XIV) vith a compound of the formula (XV):
NH2CH2CH2OH (XIV) H0 \ / CH2COr4 · (XV)
For example this reaction may be performed using the Hitsunobu reaction vith diethyl azodicarboxylate and triphenylphosphine. Desirably the amino function (and carboxy function, if present) is protected during this reaction and subsequently deprotected in conventional manner. Examples of a suitable protecting group for the amino function include the phthaloyl and t-butoxycarbonyl groups. The compounds of the formula (XV) may be prepared according to methods known in the art.
rοεοοο^Α
- 14 The compound of the formula (VI) may be hydrolysed to 4-[2-(2-hydroxy-2-phenylethylamin<f)ethoxy]phenylacetic acid or a bioprecursor thereof under conditions knovn in the beta adrenergic blocker art; for example via alkaline hydrolysis in a suitable solvent.
The compounds of the formula (VI) may be prepared by the reaction of a compound of the formula (XV) vith a compound of the formula (XVI):
wherein R? is a group -CE^CI^OH. This reaction may be performed in any conventional manner for example by a method analogous to the reaction of the compounds of the formulae (XIV) and (XV). In an alternative the compounds of the formula (VI) may be prepared by the reaction of a compound of the formula (XVI) wherein R? is hydrogen vith a compound of the formula (IX) as hereinbefore described. In a further alternative the compounds of the formula (VI) may be prepared by the reaction of a compound (III) vith a compound of the formula (XVII):
r8oocnhch2ch2o
ch2cor4 (XVII)
8 wherein COR is as hereinbefore defined and R 0- is a leaving group, g
for example R 0- is ^alkoxy.
The compound of the formula (XVI) wherein R? is -CH2CH2OB may be prepared for example by reaction of a compound of the formula (III) with an N-alkoxycarbonyl derivative of a compound of the formula (XIV) wherein the hydroxy group is optionally protected for example the
AP Ο Ο Ο 3 Ο 1
- 15 tetrahydropyranyl ether of t-butoxycarbonylaminoethanol. The compounds of the formula (XVI) wherein R? is hydrogen are obtainable in conventional manner. The compounds of the formulae (IX) and (XVII) may be obtained by alkylation of the compounds of the formula (XV) in conventional manner.
The reaction between the compounds of the formulae (VIII) and* (IX) is conveniently performed under conditions analogous to the reaction between a compound (IV) and a compound of the formula (V). L' may have similar values as recited hereinabove for L.
In the compounds of the formula (VII) examples of 5 12 hydrolysable groups R include alkoxy and -NR R groups so that
-COR^ represents a ^alkyl ester or an amide function. Such groups may be hydrolysed (acidic, basic, enzymatic) to a group -C09H under conventional conditions. Conversions wherein R is an in vivo hydrolysable moiety also represent examples of interconversions of a bioprecursor of 4-(2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid into 4-[2-(2-hydroxy-2-phenylethylamino)ethoxylphenylacetic acid. Suitable acid conditions are for example a strong mineral acid such as hydrochloric, sulphuric or phosphoric acid, conveniently at a temperature in the range, for example, 20’ to 110’C and in a polar solvent, such as water, a C^_^alkanol (for example methanol or ethanol) or acetic acid. In such cases, the corresponding mineral acid salt of 4-(2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetic acid may be conveniently isolated. Alternatively, base conditions may be used, for· example lithium, sodium or potassium hydroxide, conveniently in a suitable solvent or diluent such as an aqueous ^alkanol at a temperature in the range, for example, 10’ to 110’C; or an alkali halide for example lithium chloride in a polar solvent such as dimethylsulphoxide. As yet further alternatives, when -COR^ is £-butoxycarbonyl, the decomposition may be carried out, for example, by thermolysis at a temperature in the range, for example, 100 to 220*C, alone or in the presence of a suitable diluent such as diphenyl ether.
f ο ί 0 C 0 HA
- 16 The compounds of the formula (VII) may be prepared by methods analogous to those described hereinabove for 4-(2-(2-hydroxy-2phenylethylamino)ethoxyjphenylacetic acid or a bioprecursor thereof, vith optional protection of the amino function for example vith a benzyl group.
4-(2-(2-Hydroxy-2-phenylethylamino)ethoxyJphenylacetic acid and amide bioprecursors thereof may be converted to ester precursors thereof. Suitable conditions are, for example, refluxing in the corresponding alkanol under acidic conditions, for example, vith the addition of concentrated sulphuric acid as a catalyst.
The reduction of the compounds (XI), (XII) and (XIII) may be carried out by conventional chemical or catalytic methods, such as chemical reduction using sodium borohydride or by catalytic hydrogenation using catalysts such as palladium on charcoal, or platinum.
Reduction by sodium borohydride is conveniently carried out in an alcohol such as methanol and the reaction is generally carried out at from 0 - 20°C.
Catalytic reduction is conveniently carried out in a conventional hydrogenation solvent such as an alcohol, for example ethanol. The hydrogenation is generally carried out under hydrogen gas at about 1 to about 10 atmosphere pressure and at ambient or elevated temperature.
Compounds of the formula (XI) may be prepared by the reaction of a compound of the formula (V) vith a compound of the formula (XVIII):
COCH2L'' (XVIII)
APO 00 30 1
- 17 wherein L'' is a displaceable group.
*
The reaction between a compound of the formula (XVIII) and a compound of the formula (V) may be performed in a suitable solvent such as an alcohol or an ether, for example methanol or diethyl ether, at a1 temperature in the range, for example, -10 to 110’C and most conveniently at ambient temperature. In the compounds of the formula a (XVIII), L may be, for example, halogen such as chloro or bromo.
The resulting compounds of the formula (XI) may be converted into 4-{2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetic acid or bioprecursors thereof in situ.
The compounds of the formula (XVIII) may be prepared by methods knovn in the art.
Compounds of the formula (XII) may be prepared by reacting a compound (XIX) vith a compound of the formula (V):
COCHO (XIX)
The reaction between a compound (XIX) vith a compound of theformula (V) may be performed in a suitable solvent such as an alcohol,for example, ethanol at a temperature range, for example, 0-80°C and most conveniently at ambient temperature. The resulting compounds of the formula (XII) may be converted into 4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid or bioprecursors thereof in situ.
Compounds of the formula (XIII) may be prepared by reacting compounds of the formula (XX) with a compound of the formula (VIII):
r ο?, ο ο η AA
- 18 OHCCH2O
(XX) vherein COR is as hereinbefore defined.
The reaction betveen a compound of the formula (XX) and a compound (VIII) may be performed in a suitable solvent such as an alcohol, for example, ethanol, at a temperature in the range, for example, 0 - 80°C and most conveniently at ambient temperature. The resulting compounds of the formula (XIII) may be converted into
4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid or bioprecursors thereof in situ.
Compounds of the formula (XX) may be prepared by hydrolysis of a compound of the formula (XXI):
\HCH,0-// X\-CH9COR4 (XXI) „10/ W
9 10 vherein COR is as hereinbefore defined and R and R are independently hydrogen or C^ ^alkyl. Suitable conditions for hydrolysis are, for example, a strong mineral acid such as hydrochloric or sulphuric; conveniently at a temperature range, for example, 20 110°C, in a suitable solvent such as tetrahydrofuran, dichloromethane or diethyl ether.
Compounds of the formula (XXI) may be prepared by standard methods knovn in the art. For example, by reacting a compound of the formula (XXII) vith a compound of the formula (XV) in the presence of a mild base:
APO 00 3Ο 1
HCH2L' (XXII)
R*“0
10 wherein R and R are as hereinbefore defined and L' is a displaceable group.
Suitable conditions include heating in a suitable solvent such as dichloromethane, in the presence of a mild base, for example sodium carbonate. In a compound of the formula (XXII) L' may be, for example, halogen such as bromo.
The compounds of the formulae (VI), (VII), (X), (XI), (XII) and (XIII) are novel and form another aspect of the invention.
Bioprecursor esters of the hydroxy group may be prepared in conventional manner for example by reacting the hydroxy group vith an activated derivative of an acid under conditions knovn in the beta adrenergic blocker art.
Pharmaceutically acceptable salts may be prepared by reacting 4-(2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid or a bioprecursor thereof vith the appropriate acid or base in conventional manner. Alternatively vhen a hydrogen halide salt is required, it may^ conveniently be obtained by hydrogenation of the free base together Evith a stoichiometric amount of the corresponding benzyl halide. ~
The following biological test methods, data and Examples serve to illustrate this invention.
-t £
Thermogenic effects
The thermogenic effects of compounds of the formula (I) and bioprecursors thereof may be demonstrated using one or more of the following standard tests:ι c ?. ο ο n RA
- 20 (a) Rats are cold adapted at 4°C for 5 days to increase their capacity for thermogenesis. They are then transferred to a warm environment of 25°C for 2 days. On the folloving day, a test compound is administered sub-cutaneously or orally. Animals are sacrificed one hour later and the interscapular, brovn adipose tissue (BAT) pad is removed. BAT mitochondria are prepared by differential centrifugation and GDP binding is determined (Hollovay et al., International Journal of Obesity, 1984, 8, 295) as a measure of thermogenic activation. Each test includes a control vhich is dosed vith the solution/suspension . vehicle only and a positive control vhich is dosed vith isoprenaline (as its sulphate) at lmgkg'*1. Test compounds are routinely dosed at 0.1, 0.3, 1.0, 3.0, and 10 mgkg-1 and results expressed in terms of the effect on GDP binding produced by the positive control. Prom these results, a dose (Εϋ^θ) necessary to produce 50X of the isoprenaline effect is calculated by curve fitting. Compounds are considered active in this test if they cause a significant elevation in GDP binding as compared to controls.
(b) Rats are adapted to a thermoneutral environment (29eC) for 2 weeks in order to decrease their capacity for BAT mediated nonshivering thermogenesis. During the final 5 days the animals are trained to use an apparatus for measuring heart rate non-invasively via foot-pad electrodes connected to an ECG integrator giving a continuous read-out of heart rate. A test compound is administered sub-cutaneously or orally at the Εϋ^θ determined in test (a), and heart rate is determined 15-30 minutes after dosing. The procedure is then repeated in subsequent tests using increasing multiples of the ED^q determined in test (a) until the heart rate (HR) reaches or exceeds 500 beats per minute, or until the dose reaches 100 times the ED^q determined in test (a). The dose necessary to produce a heart rate of 500 beats per minute (ϋ^θθ dose) is estimated.
The ratio of to Εϋ^θ in test (a) can be defined as the selectivity index (SI) and provides a measure of the selectivity of the compound for BAT as opposed to the cardiovascular system. Compounds are considered to have significant selectivity vhich have an
AP Ο Ο Ο 3 Ο 1
- 21 SI of >1. Non-selective compounds have an SI of <1 (for example isoprenaline » 0.06).
(c) Rats are kept at 23°C for at least tvo days, then fasted overnight. On the folloving day, the basal metabolic rate of the animals is determined using a close-circuit oxygen consumption apparatus of the type described by Arundel et al., 1984, J. Appl. *
Physiol. Respirat. Environ. Exercise Physiol., 1984, 57 (5) 1591-1593. The rats are then dosed (orally) vith test compound at about 1 rngkg^ as a solution or suspension in 0.025X v/v Polysorbate 80 (0.5ml/100g). Metabolic rate is then determined for at least one hour after dosing. Compounds are considered active in this test if they cause a significant increase in metabolic rate as compared to control animals (Student's t test: p <0.05) dosed only the solution or suspension vehicle.
In the above tests, the compounds of the formula (I) in general produce effects of the folloving order vithout producing overt toxicity:test (a): sub-cutaneous or oral Εϋ^θ for GDP binding in BAT mitochondria of 0.01-10 mgkg-^; test (b): show an SI of >50; and test (c): show 2-9ml 0j min“^(Kg®’2^j-l at ingfcg-* p.o.
By way of illustration, the compound described in the accompanying Example 1, produces the folloving effects in the above tests:(a) oral ED5Q 0.55mgkg_1;
(b) SI >50 (oral);
(c) 6.53 ml O2 min at lmgkg-^ p.o.
f ο ί Ο 0 0 RA
- 22 Oral glucose tolerance test *
Male rats (125-15Og) were fasted for 24 hours. After fasting, a group of six rats was anaesthetised and a cardiac blood sample taken. Other groups of rats were then dosed with the compound of Example 1 (5.0 mg/Kg p.o.) dissolved in an aqueous solution of 0.025% polysorbate. Control rats were dosed with polysorbate solution alone. The volume of solution dosed was 0.5ml/100g body weight. 60 minutes subsequent to dosing six control and six treated rats were anaesthetised and cardiac samples taken. The remaining rats were given an oral glucose load (lg/Kg) dosed as a 20% solution of D-glucose (0.5ml/100g). Groups of six rats for each control and treatment were then anaesthetised and bled at 20, 60 and 120 minutes after the glucose load. Plasma glucose and insulin were determined using standard methods.
Results Plasma glucose (mM)
Time relative to oral glucose load (mins) Control Example 1 5mg/Kg p.o.
-30 6.35±0.26
0 6.13±0.21 3.52±0.07 (p<0.001)
20 9.05+0.50 5.72+0.24 (p<0.001)
60 6.37+0.39 5.32+0.24 (p<0.05)
120 6.5 +0.23 5.43+0.31 (p<0.05)
The results are mean + S.E. M. of observations in six rats in each
group. Student's t test was ; used to test the significance of the
difference betveen control and treated groups. The compound of Example
possesses marked antihyperglycaemic activity.
AP000301
- 23 Effects on blood glucose levels in insulin resistant db/db mice
C57BL/KsJ (db/db) mice vere divided into tvo groups and allowed free access to control diet or diet containing the compound of Exaaple 1 at a concentration of 50mg/kg diet. A group of control (+/+) mice vas als6 included in the experiment. After 16 days treatment, blood samples were taken from the mice for determination of blood glucose levels. -E
Results
Group
Control (+/+)
Untreated (db/db)
Blood glucose (mM)
4.94±0.1
14.53±0.66 (pCO.OOl)
Compound of Example 1 5.3+0.46 (db/db)
Results are mean ± S.E.H. of observations in groups of 15 mice. Student's t test vas used to test the significance of the difference between control (+/+) and treated (db/db) groups. The compound of Example 1 normalises blood glucose levels in this animal model of insulin resistance.
Rat adipocyte lipolysis test
Epididymal adipose tissue vas excised from male rats and adipocytes prepared by digestion vith collagenase. Cells vere isolated by flotation and washed four times vith Krebs Ringer Bicarbonate buffer (KRB), finally washing in KRB containing 2% bovine serum albumin (KRB/BSA). Aliquots of the cell suspension vere incubated in the presence of a range of concentrations of the test compound in a total volume of 1ml KRB/ 2Z BSA containing 0.1 mg/ml ascorbate in an atmosphere of 95Z02,5XC02· Incubations vere also carried out in the presence of a concentration of isoprenaline r ο ε ο ο o αα
- 24 (3 χ ΙΟ^Μ) known to have a maximal effect on lipolysis. Control incubations vere carried out in KRB/ 2% BSA containing ascorbate. The incubations vere terminated after 90 minutes by placing the tubes on ice, and aliquots of infranatant removed for assay of free fatty acids vhich vere measured using a VAKO NEFA-C assay kit (Alpha
Laboratories). Lipolytic activity of the compounds vas assessed by determining the increase in free fatty acid concentrations caused by
the compounds compared to controls. The maximal effects (efficacy) the compounds vere determined and expressed as percentage of the maximal effect of isoprenaline.
Test compound Efficacy
Compound of Example 1 100%
4-(2-(2-Hydroxy-3-phenoxypropylamino)- ethoxy]phenoxyacetic acid (free carboxylic acid from USP4772631) 26%
Efficacy is the maximal effect of the test compound on lipolysis expressed as a percentage of the maximal effect of isoprenaline.
Comparative test on GDP potency
In another comparative test the potency of the compound of Example 1 in test a) above vas compared vith a reference compound
Compound EDca (oral) υ -1
Example 1 0.55
4-[2-(2-Hydroxy-2-phenylethyl- amino)ethoxyJphenyloxyacetic acid (within the scope of EP-A 23385) >3.00
AP 0 0 0 3 0 1
- 25 The invention vill nov be illustrated by the folloving Examples in vhich, unless othervise stated:
a) chromatography vas performed on Kieselgel (Art 9385; 230-400 Mesh) obtainable from E. Merck, Darmstadt, Federal Republic of Germany.
b) evaporations vere carried out under reduced pressure using a rotary evaporator.
c) melting-points are uncorrected.
Example 1 (R)-4-[2-(2-Hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid (R)-4-{2-(2-Hydroxy-2-phenylethylamino)ethoxy]phenylacetamide hydrochloride (3.5g) vas heated on the steam bath for tvo hours in 2N HC1 (100ml). The reaction mixture vas filtered, cooled and the solid collected by filtration. The solid vas crystallised from vater to give (R)-4-[2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetic acid as the hydrochloride (2.5g), mp 207-209eC; microanalysis: found C, 61.5, H, 6.5; N, 3.8; Cl, 10.IX; required for C18H22C1NO4: C, 61.5; H, 6.3; N, 4.0; Cl, 10.IX; («]25D- - 27.3° (c 0.99 in methanol).
The product hydrochloride described above (lg) vas dissolved in distilled vater (50ml) at room temperature and then the pH vas carefully adjusted to pH 6.7 by the addition of 2N NaOH. The solid vhich separated vas (R)-4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid (0.8g), m.p. 209-211°C; microanalysis: found, C,
68.4; H, 6.8; Ν, 4.5X; required for C^gH^NO^: C, 68.6; H, 6.7; N,
4.5X (α]25θ= -30.1° (c, 1.0 in acetic acid).
r ο εο ο ο 9Α
- 26 In an alternative, the product may be obtained by acid hydrolysis, in similar manner to that above, of (R)-4-[2-(2-hydroxy2-phenylethylamino)ethoxy(phenylacetamide vith recrystallisation from vater.
Example 2 (R)-4-[2-(2-Hydroxy-2-phenylethylamino)ethoxy(phenylacetamide (R)-4-(2-(N-Benzyl-N-(2-hydroxy-2-phenylethyl)amino)ethoxy]phenylacetamide (12.9g) vas dissolved in ethanol (150ml) and glacial acetic acid (50ml). The solution obtained vas hydrogenated in the presence of 10% v/v palladium on carbon (l.Og) at about 20 bar and 60° for 24 hours. The mixture vas cooled, filtered and the filtrate vas evaporated under reduced pressure. 1.2g of the residual oil (9.8g) thus obtained vas dissolved in ethyl acetate and treated vith a solution of ether saturated vith hydrogen chloride. The precipitated solid vas crystallised from methanol to give (R)-4-(2-(2-hydroxy-2phenylethylamino)ethoxy(phenylacetamide hydrochloride (0.8g), mp 255-257eC; microanalysis: found C, 61.3; H, 6.3; N, 8.0; Cl, 10.2% required for C18H23C1N2°3: C, 61.6; H 6.6; N, 8.0; Cl, 10.1%; [<x]23D = -19.5°(c « 1.0 in DMSO). This reaction may also be performed in aqueous isopropanol containing glacial acetic acid (1 equivalent) at ambient temperature and pressure.
The starting material vas prepared as follovs:
A mixture of 4-[2-(benzylamino)ethoxy]phenylacetamide (OLS 2135678) (14.Og), (R)-styrene oxide (5.92g) and propan-2-ol (200ml) vas heated under reflux for 72 hours. The mixture vas cooled and the solvent evaporated under reduced pressure. The residue vas purified by dry, flash column chromatography. Elution vith 10% methanol in dichloromethane gave (R)-4-[2-(N-benzyl-N-(2-hydroxy-2-phenylethyl)amino)ethoxy(phenylacetamide as an oil (12.9g). This reaction may also be performed in t-amyl alcohol under reflux.
AP Ο Ο Ο 3 Ο 1
- 27 Example 3 (R)-Methyl 4-(2-(2-hydroxy-2-phenylethylamino)ethoxy(phenylacetate (R)-4-( 2-(2-Hydroxy-2-phenylethylamino)ethoxy (phenyl- 2 acetamide hydrochloride (0.45g) vas heated under reflux in methanol 3 (20ml) containing concentrated sulphuric acid (0.5ml) for 18 hours. 11 The mixture vas cooled and the solvent evaporated under reduced pressure. The residue vas dissolved in dichloromethane (30ml) and washed successively vith vater (20ml), 5X NaHCO^ solution (50ml) and vater (20ml), dried over MgSO^ and then the solvent vas removed under reduced pressure. The residue vas dissolved in methyl acetate (20ml) and treated vith a solution of ether saturated vith hydrogen chloride. The precipitated solid vas crystallised from a mixture of methanol and methyl acetate to give (R)-methyl 4-[2-(2-hydroxy-2-phenylethylamino)ethoxy(phenylacetate hydrochloride (0.25g), m.p. 181-183’C;
microanalysis: found, C, 62.6; H, 6.6; N, 3.8; Cl, 9.9X; required for C19H24C1NO4: C, 62.4; H, 6.6; N, 3.8; Cl, 9.7X; [<x(25D« - 25.3°(c »
0.99 in methanol).
Example 4
4-(2-(2-Hydroxy-2-phenylethylamino)ethoxy (phenylacetic acid
4-(2-(2-Hydroxy-2-phenylethylamino)ethoxyIphenylacetamide hydrochloride (2.8g) vas heated on the steam-bath for 4 hours in 4N HC1 (60ml). The reaction mixture vas filtered, cooled and the solid Λ collected by filtration vas 4-[2-(2-hydroxy-2-phenylethylamino)~ ~ ethoxy(phenylacetic acid as the hydrochloride (1.4g), m.p. 183-184eC (softens at about 178°C): microanalysis: found C, 61.4; B, 6.3; H,
4.1; Cl, 10.3Z; required for C^H^CINO*: C, 61.5; H, 6.3; N, 4.0; Cl 10.IX.
ο ε ο ο o q/
- 28 Example 5
4-[2-(2-Hydroxy-2-phenylethylamino)ethoxyIphenylacetamide
A preformed solution of 4-[2-(N-benzyl-N-(2-hydroxy-2phenylethyl)amino)ethoxyJphenylacetamide in propan-2-ol and glacial acetic acid (see below) vas hydrogenated in the presence of 10X v/v palladium on carbon (l.Og) at about 20 bar and 60®C for 12 hours. The mixture vas cooled, filtered and the filtrate vas evaporated under reduced pressure. The residual oil thus obtained vas dissolved in ethyl acetate and treated vith a solution of ether saturated vith hydrogen chloride. The precipitated solid vas crystallised from methanol to give 4-[2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetamide hydrochloride (6.8g), m.p. 250-251eC (softens at about 248*C); microanalysis: found C, 61.2; B, 6.5; N, 8.3; Cl,
10.3X; required for C^^^Cl^O^: C, 61.6; H, 6.6; N, 8.0; Cl, 10.IX.
The starting material vas prepared as follows:
A mixture of 4-(2-N-benzylaminoethoxyJphenylacetamide (OLS 2135678) (5.68g), styrene oxide (2.4g) and propan-2-ol (100ml) vas heated under reflux for 72 hours. The thus formed 4-(2-(N-benzylN-(2-hydroxy-2-phenylethyl)amino)ethoxyJphenylacetamide vas cooled and diluted vith propan-2-ol (30ml) and glacial acetic acid (20ml).
An alternative method for preparing the title compound is: 2-Hydroxy-2-phenylethylamine (1.91g), 4-(2-bromoethoxyJphenylacetamide (3.59g) and triethylamine (i.41g) in ethanol (450ml) vere heated under reflux for 24 hours and then the solution vas cooled and filtered to remove a little insoluble material (0.2g). The solvent vas removed from the filtrate under reduced pressure and the residual solid vas triturated vith a little vater, isolated by filtration and dried. The solid (3.1g) vas dissolved in methanol (100ml) and treated vith a solution of ether saturated vith hydrogen chloride. The precipitated
AP 0 00 30 1
- 29 solid vas crystallised from methanol to give 4-(2-(2-hydroxy-2-phenyl ethylamino)ethoxy]phenylacetamide*hydrochloride m.p. and mixed m.p. 250-251’C.
A further alternative method for preparing the title compound is:
Phenacyl bromide (0.49g), 4-(2-aminoethoxy)phenylacetaoide (0.49g), potassium carbonate (0.35g) and methanol (20ml) vere heated under reflux for 2 hours, cooled to ambient temperature and stirred whilst sodium borohydride (l.Og) vas added in small portions during 1 hour. Stirring vas continued for 18 hours and then the solvent vas evaporated under reduced pressure. The residue vas partitioned betveen dichloromethane (20ml) and vater (10ml). The aqueous layer vas separated and extracted vith dichloromethane (20ml). The combined dichloromethane extracts vere washed vith vater (20ml), dried over MgSO^ and evaporated. The residual gum vas dissolved in ethyl acetate and treated vith a solution of ether saturated vith hydrogen chloride. The precipitated solid vas crystallised from a mixture of methanol and ethyl acetate to give 4-(2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetamide hydrochloride m.p. and mixed m.p. 248-25O°C.
A yet further alternative method for preparing the title compound is:
Phenylglyoxal hydrate (O.57g) and 4-(2-aminoethoxy)phenylacetamide (0.49g) in methanol (15ml) vere heated on the steam bath to obtain a clear solution. This vas then cooled in an ice-bath and sodium borohydride (lg) vas added in small portions during 1 hour vith stirring. After about lOOmg of sodium borohydride had been added a vhite solid began to separate and this vas redissolved by the addition of further methanol (35ml). The mixture vas stirred at ambient temperature for 18 hours and then the solvent vas evaporated under reduced pressure. The residual solid vas treated vith dichloromethane (20ml) and vater (20ml) and that solid vhich did not go into solution vas isolated by filtration. This solid vas dissolved in methanol (20ml) and treated vith a solution of ether t ο ε ο ο o ha
- 30 saturated vith hydrogen chloride. The bulk of the solvent vas evaporated and ethyl acetate (20ml) vas added to precipitate the title compound as hydrochloride m.p. and mixed m.p. 25O-251°C.
Example 6
Methyl 4-[2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetate
4-(2-(2-Hydroxy-2-phenylethylamino)ethoxyJphenylacetamide hydrochloride (2.5g) vas heated under reflux in methanol (50ml) containing concentrated sulphuric acid (1.5ml) for 24 hours. The mixture vas cooled and the solvent evaporated under reduced pressure. The residue vas partitioned betveen dichloromethane (150ml) and 5X NaHC0.j solution (150ml). The organic layer vas separated and vashed successively vith 5X NaflCO^ solution (20ml) and water (20ml), dried over MgSO^ and then the solvent vas removed under reduced pressure.
The residue vas dissolved in methyl acetate (40ml) and treated vith a solution of ether saturated vith hydrogen chloride. The precipitated solid vas crystallised from a mixture of methanol and methyl acetate to give methyl 4-[2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetate hydrochloride (1.8g), m.p. 169-171°C; microanalysis: found C, 62.5; H, 6.6; N, 3.8; Cl, 9.7X; required for C^H^CINO*: C, 62.4; H, 6.6; N, 3.8; Cl, 9.7X.
Example 7 (R)-4-(2-(2-Acetoxy-2-phenylethylamino)ethoxyJphenylacetic acid
A solution of N-t-butoxycarbonyl-(R)-4-(2-(2-acetoxy-2phenylethylamino)ethoxyJphenylacetic acid (500mg) in a mixture of dichloromethane (5ml) and trifluoroacetic acid (5ml) vas allowed to stand for 90 minutes at 20eC. The solvent vas removed under reduced pressure and the residue vas dissolved in ethanol (5ml). The solution vas cooled to -20eC and ethereal hydrogen chloride vas added to yield white crystals of the title compound as the hydrochloride (300mg);
m.p. 158-160’C; (<xj -35.4° (c = 1.0 in methanol); microanalysis:
AP Ο Ο Ο 3 Ο 1
- 31 found C, 60.2; Η, 6.5; Ν, 3.4; ϊ^Ο, 0.9Χ; required for (^θΗ^ΟίΝΟ^
0.25 Η20: C, 60.3; Η, 6.2; Ν, 3.5;‘ Η20 1.1Χ.
The starting material vas prepared as follows:
a) Di-t-butyl dicarbonate (1.25g) in t-butanol (15ml) vas adde<£ to a stirred solution of (R)-4-[2-(2-hydroxy-2-phenylethylamino)- ·* ethoxyJphenylacetic acid hydrochloride (2.0g) in IN aqueous sodium a hydroxide (30ml). The reaction mixture vas stirred for 90 minutes at 20°C. The solvent vas removed under reduced pressure. Vater (20ml) vas added to the residue and the solution vas acidified vith 2N aqueous citric acid. The product vas extracted into 5X methanol in dichioromethane (5 x 20ml). The extracts vere dried and the solvent removed under reduced pressure to yield N-t-butoxycarbonyl-(R)4-[2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetic acid as a glass (1.3g); [aj3^^ + 6.2° (c » 1.0 in methanol).
b) A solution of the product from a) above in pyridine (2.5ml) and acetic anhydride (2.5ml) vas allowed to stand for 16 hours at
20eC. The solvent mixture vas removed under reduced pressure. The residue vas dissolved in dichioromethane (20ml). The solution vas vashed vith vater (3 x 10ml), dried, and the solvent removed under reduced pressure to give a viscous oil (1.3g). A solution of the oil (1.3g) in a mixture of dioxan (10ml) and vater (6ml) vas stirred under reflux for 2 hours. The solvent vas removed under reduced pressure and the residue was subjected to chromatography using 10X methanol in dichioromethane as eluant. The appropriate fractions vere combined to yield N-t-butoxycarbonyl-(R)-4-(2-(2-acetoxy-2-phenylethylamino)25 ethoxyJphenylacetic acid as a viscous oil (500mg); (aj θ = -16.8° (c = 1.0 in dichioromethane).
Example 8
As stated previously, suitable pharmaceutical compositions of compounds of formula (I) defined hereinbefore may be obtained by standard formulation techniques.
t ο δ ο η υ
- 32 A typical tablet formulation suitable for oral administration to varm-blooded animals comprises as active ingredient a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore (for example as described in one of the preceding Examples), and may be produced by aqueous granulation or direct compression together vith milled lactose containing a standard disintegrant and/or lubricant. Vhen tablets containing small amounts of active ingredient (for example 0.5-10 mg) are required, the direct compression method may be used vherein the active ingredient is mixed vith lactose in the ratio of 1:10 parts by veight and/or microcrystalline cellulose containing 0.5Z by veight of a lubricant (such as magnesium stearate) and 5Z by veight of a disintegrant (such as cross-linked sodium carboxymethyl cellulose or sodium starch glycolate). An example of a tablet prepared by aqueous granulation is that containing active ingredient (50-100mg), lactose (230mg), maize starch (80mg), gelatine (2.2mg), magnesium stearate (4mg) and croscarmellose sodium (7mg).
FS36367
PMD
24APR92 flaring now partfcvbrly dc^nbefi ιΛί An ft Λ Λ T Λ 4 a*, er tinned nr·’ n.r Η ’ r ή acd Ια V v U v V I *H4t πι.ιηη;' :c .< periormoi l/*e deeiaec <u «t i, *e cUuru w ·—

Claims (14)

1. A compound of the formula (I):
ch(oh)ch2nhch2cb2 or a bioprecursor or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 vhen in the form of a carboxylic acid or pharmaceutically acceptable salt thereof.
3. A compound according to claim 2 in the form of a salt formed vith hydrochloric acid.
4. A compound according to claim 1 of the formula (II):
ch(oh)ch2nhch2ch2o ch2cor4 (II) vherein R is C^galkoxy, or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 4 vherein R is methoxy.
6. A compound according to claim 1 vhich is:
(R)-4-(2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacet ic acid; (R)-4-(2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetamide; (R)-methyl 4-(2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetate;
4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid;
4-(2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetamide; or <
Cl
C C 0 ‘LA
- 34 methyl 4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetate; or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition vhich comprises a compound according to claim 1 or a bioprecursor or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
8. A process for preparing a compound according to claim 1 vhich process comprises:
a) reacting a compound (III) or (IV) vith a compound of the formula (V):
NH2CH2CH2O
CH2COR4 (III) (IV) (V) vherein -COR is carboxy or its bioprecursor and L is a displaceable group; or
AP Ο Ο Ο 3 Ο 1
- 35 b) hydrolysis of a compound of the formula (VI):
CH ^zNCH2CH20 CH„
CH2COR (VI) wherein COR is as hereinbefore defined; or
c) for 4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid hydrolysing a compound of the formula (VII):
ch(oh)ch2nhch2ch2o- ch2cor· (VII) wherein R^ is a hydrolysable group;
d) reacting a compound of the formula (VIII) with a compound of the formula (IX):
CH(OH)CH2NH2 l'ch2ch2o ch2cor4 (VIII) (IX)
- 36 4 wherein -COR is as hereinbefore defined and L' is a displaceable group;
deprotecting a compound of the formula (X):
CH(OH)CH2NHCH2CH2O CH2R6 (X)
6 4 wherein R is a protected derivative of a group -COR ;
f)
f)
g)
g) converting 4-12-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid into a bioprecursor, or vice versa, or converting a bioprecursor of 4-[2-(2-hydroxy-2-phenylethylamino)ethoxy]phenylacetic acid into another bioprecursor of 4-[2-(2-hydroxy-2-phenylethylamino)ethoxyJphenylacetic acid;
reducing a compound of the formula (XI):
(XI) wherein -COR^ is as hereinbefore defined;
reducing a compound of the formula (XII):
(XII) wherein -COR^ is as hereinbefore defined;
AP Ο Ο Ο 3 Ο 1
- 37 i) reducing a compound of the formula (XIII):
CH(OH)CH2N«CHCH2O (XIII) vherein COR is as hereinbefore defined;
and vherein any functional group is optionally protected and thereafter if necessary;
(i) removing any protecting groups;
(ii) forming a pharmaceutically acceptable salt.
9. A compound of the formula (VI), (X), (XI), (XII) or (XIII) as defined in claim 8.
10. A compound of the formula:
_ch(oh)ch2nhch2ch2o CH2C0NH2
11. The use of a compound according to claim 1 or a bioprecursor or a pharmaceutically acceptable salt thereof in a method of treating disease conditions mediated through &-adrenoceptors.
12. The use of a compound according to claim 1 or a bioprecursor or a pharmaceutically acceptable salt thereof in a method of stimulating thermogenesis and/or improving glucose tolerance.
- 38
13. The use of a compound according to claim 1 cr a bioprecursor or a pharmaceutically acceptable salt thereof in a method of treating obesity, mature onset diabetes, NIDDM, hypertension and/or hyperlipidaemia.
14. The use of a compound according to claim 1 or a bioprecursor or a pharmaceutically acceptable salt thereof in a method of treating hypertriglyceridaemia, hypercholesterolaemia, atherosclerotic disease and conditions of-lov HDL levels.
APAP/P/1992/000385A 1991-05-28 1992-05-18 "4-(2-(2-Hydroxy-2-phenylethylamino) ethoxy)phenylacetic acid,derivatives for use in the treatment of obesity and related conditions. AP301A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB919111426A GB9111426D0 (en) 1991-05-28 1991-05-28 Chemical compounds

Publications (2)

Publication Number Publication Date
AP9200385A0 AP9200385A0 (en) 1992-07-31
AP301A true AP301A (en) 1994-01-21

Family

ID=10695679

Family Applications (1)

Application Number Title Priority Date Filing Date
APAP/P/1992/000385A AP301A (en) 1991-05-28 1992-05-18 "4-(2-(2-Hydroxy-2-phenylethylamino) ethoxy)phenylacetic acid,derivatives for use in the treatment of obesity and related conditions.

Country Status (31)

Country Link
US (3) US5393779A (en)
EP (1) EP0516349B1 (en)
JP (1) JP3232337B2 (en)
KR (1) KR920021492A (en)
CN (1) CN1031564C (en)
AP (1) AP301A (en)
AT (1) ATE128115T1 (en)
AU (1) AU652826B2 (en)
BR (1) BR9202002A (en)
CA (1) CA2068377A1 (en)
CS (1) CS159292A3 (en)
DE (1) DE69204906T2 (en)
DK (1) DK0516349T3 (en)
ES (1) ES2076688T3 (en)
FI (1) FI922424A (en)
GB (2) GB9111426D0 (en)
GR (1) GR3017462T3 (en)
HU (2) HU211401B (en)
IE (1) IE69043B1 (en)
IL (1) IL101821A0 (en)
MY (1) MY136249A (en)
NO (1) NO922113L (en)
NZ (1) NZ242643A (en)
OA (1) OA10077A (en)
PL (1) PL294704A1 (en)
RO (1) RO111569B1 (en)
RU (1) RU2073666C1 (en)
SI (1) SI9200093A (en)
TW (1) TW198709B (en)
YU (1) YU54592A (en)
ZA (1) ZA923356B (en)

Families Citing this family (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NO179246C (en) * 1991-11-20 1996-09-04 Sankyo Co Aromatic amino-alcohol derivatives and intermediates for their preparation
US6696486B1 (en) * 1992-01-22 2004-02-24 Glaxo Group Limited Medical use for atypical β-adrenoceptor agonists
ES2174897T3 (en) * 1992-01-22 2002-11-16 Glaxo Group Ltd MEDICAL USE OF ATIPIC BETA-ADRENOCEPTORS AGONISTS.
GB9207964D0 (en) * 1992-04-10 1992-05-27 Ici Plc Chemical compounds
GB9209076D0 (en) * 1992-04-27 1992-06-10 Ici Plc Chemical compounds
US5662934A (en) * 1993-01-05 1997-09-02 Najarian; Thomas Compositions and methods for lowering cholesterol while maintaining antioxidant levels
GB9313574D0 (en) * 1993-07-01 1993-08-18 Glaxo Group Ltd Medicaments
US5482971A (en) * 1993-10-01 1996-01-09 American Cyanamid Company Beta3 -adrenergic agents and their use in pharmaceutical compositions
US5578638A (en) * 1993-11-05 1996-11-26 American Cyanamid Company Treatment of glaucoma and ocular hypertension with β3 -adrenergic agonists
US5563171A (en) * 1993-11-05 1996-10-08 American Cyanamid Company Treatment of glaucoma and ocular hypertension with β3-adrenergic agonists
US5561142A (en) * 1994-04-26 1996-10-01 Merck & Co., Inc. Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity
US5541197A (en) * 1994-04-26 1996-07-30 Merck & Co., Inc. Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity
US5627200A (en) * 1994-09-26 1997-05-06 Pfizer Inc β3 -Adrenoceptor agonists and antagonists for the treatment of intestinal motility disorders, depression, prostate disease and dyslipidemia
US6020382A (en) * 1996-02-02 2000-02-01 Merck & Co., Inc. Method of treating diabetes and related disease states
US6090836A (en) * 1996-02-02 2000-07-18 Merck & Co., Inc. Benzisoxazole-derived antidiabetic compounds
US5847008A (en) * 1996-02-02 1998-12-08 Merck & Co., Inc. Method of treating diabetes and related disease states
US5859051A (en) * 1996-02-02 1999-01-12 Merck & Co., Inc. Antidiabetic agents
US6090839A (en) * 1996-12-23 2000-07-18 Merck & Co., Inc. Antidiabetic agents
US6160000A (en) * 1996-12-23 2000-12-12 Merck & Co., Inc. Antidiabetic agents based on aryl and heteroarylacetic acids
US6329403B1 (en) 1998-06-30 2001-12-11 Takeda Chemical Industries, Ltd. Pharmaceutical composition for the treatment of diabetes
WO2001054728A1 (en) * 2000-01-28 2001-08-02 Asahi Kasei Kabushiki Kaisha NOVEL REMEDIES WITH THE USE OF β3 AGONIST
US6987131B1 (en) 2000-06-26 2006-01-17 Burzynski Stanislaw R Phenylacetic acid compositions for treating or preventing hypercholesterolemia
ES2333337T3 (en) 2000-08-29 2010-02-19 Biocon Limited USE OF A PHARMACEUTICAL COMPOSITION CONTAINING A PARAMINE-AMINOPHENYLACETIC ACID DERIVATIVE TO TREAT INFLAMMATORY AFFECTIONS OF THE GASTROINTESTINAL TRACT.
US7709677B2 (en) 2001-01-31 2010-05-04 Glaxosmithkline Llc Process of preparing arylethanoldiamines
GB0102407D0 (en) 2001-01-31 2001-03-14 Glaxo Group Ltd Process
JP2004331500A (en) * 2001-02-16 2004-11-25 Dainippon Pharmaceut Co Ltd Blood concentration-controlling preparation
EP1236723A1 (en) 2001-03-01 2002-09-04 Pfizer Products Inc. Sulfamide derivatives useful as beta3 agonists and pharmaceutical uses thereof
US8048924B2 (en) * 2001-08-29 2011-11-01 Biocon Limited Methods and compositions employing 4-aminophenylacetic acid compounds
JP2005520501A (en) 2002-02-27 2005-07-14 ファイザー・プロダクツ・インク Methods and intermediates useful for preparing β3-adrenergic receptor agonists
AU2003209527A1 (en) 2002-02-27 2003-09-09 Pfizer Products Inc. Crystal forms of (r)-2-(2-(4-oxazol-4-yl-phenoxy)-ethylamino)-1-pyridin-3-yl-ethanol
US6864268B2 (en) 2002-02-27 2005-03-08 Pfizer Inc. β3 adrenergic receptor agonists
HUE028158T2 (en) * 2004-07-07 2016-12-28 Biocon Ltd Synthesis of azo bonded immunoregulatory compounds
US9044606B2 (en) 2010-01-22 2015-06-02 Ethicon Endo-Surgery, Inc. Methods and devices for activating brown adipose tissue using electrical energy
US8476227B2 (en) 2010-01-22 2013-07-02 Ethicon Endo-Surgery, Inc. Methods of activating a melanocortin-4 receptor pathway in obese subjects
CN102633637A (en) * 2012-03-30 2012-08-15 吉林大学 Pharmaceutical formula for effectively relieving and treating constipation
US10092738B2 (en) 2014-12-29 2018-10-09 Ethicon Llc Methods and devices for inhibiting nerves when activating brown adipose tissue
US10080884B2 (en) 2014-12-29 2018-09-25 Ethicon Llc Methods and devices for activating brown adipose tissue using electrical energy

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4772631A (en) * 1985-07-30 1988-09-20 Imperial Chemical Industries Plc Phenyl ethers
WO1990013535A1 (en) * 1989-05-05 1990-11-15 Imperial Chemical Industries Plc Compounds

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1245148A (en) * 1968-11-18 1971-09-08 Pfizer Ltd Propanolamine derivatives
GB1301134A (en) * 1970-07-18 1972-12-29 Pfizer Ltd SUBSTITUTED 1-PHENYL-2-ALLYLAMINO-ALKANOLS, 1-PHENYL-2-ALLYLAMINO-ALKANES AND alpha-AMINOALKYLPHENYL KETONES
DE2965655D1 (en) * 1978-06-28 1983-07-21 Beecham Group Plc Secondary amines, their preparation, pharmaceutical compositions containing them and their use
ATE1994T1 (en) * 1979-06-16 1982-12-15 Beecham Group Plc AETHANAMINE DERIVATIVES, THEIR PREPARATION AND USE IN PHARMACEUTICAL COMPOSITIONS.
ATE1899T1 (en) * 1979-06-16 1982-12-15 Beecham Group Plc SECONDARY AMINES, THEIR PRODUCTION AND USE IN PHARMACEUTICAL COMPOSITIONS.
EP0025331B1 (en) * 1979-09-06 1983-03-02 Beecham Group Plc Cinnamic acid derivatives, their preparation, and pharmaceutical compositions containing them
DE3061693D1 (en) * 1979-10-25 1983-02-24 Beecham Group Plc Secondary amines, their preparation and use in pharmaceutical compositions
EP0040000B1 (en) * 1980-05-08 1983-10-12 Beecham Group Plc Arylethanolamine derivatives, their preparation and use in pharmaceutical compositions
DE3260490D1 (en) * 1981-03-31 1984-09-06 Beecham Group Plc Secondary amines, their preparation, pharmaceutical compositions containing them and their use
EP0063004A1 (en) * 1981-04-09 1982-10-20 Beecham Group Plc Secondary amines, processes for their preparation, and pharmaceutical compositions containing them
IT1204416B (en) * 1986-06-27 1989-03-01 Midy Spa PHENYLETHANOLAMINE ANALOGUE-BASED DRUGS FOR THE TREATMENT OF GASTRO-INTESTINAL AND UTERINE DISORDERS
GB8714901D0 (en) * 1986-07-23 1987-07-29 Ici Plc Amide derivatives
GB2212801A (en) * 1987-11-26 1989-08-02 Resolution Chemicals Limited Preparation of an alkanolamine derivatives
GB8801306D0 (en) * 1988-01-21 1988-02-17 Ici Plc Chemical compounds
EP0403360B1 (en) * 1989-06-13 1996-10-16 Sanofi Use of phenylethanolamines for the preparation of a medicament for treating ophthalmologic disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4772631A (en) * 1985-07-30 1988-09-20 Imperial Chemical Industries Plc Phenyl ethers
WO1990013535A1 (en) * 1989-05-05 1990-11-15 Imperial Chemical Industries Plc Compounds

Also Published As

Publication number Publication date
HU210799A9 (en) 1995-07-28
DE69204906D1 (en) 1995-10-26
OA10077A (en) 1996-12-18
AU652826B2 (en) 1994-09-08
AU1704492A (en) 1992-12-03
NO922113D0 (en) 1992-05-27
EP0516349B1 (en) 1995-09-20
GR3017462T3 (en) 1995-12-31
KR920021492A (en) 1992-12-18
RU2073666C1 (en) 1997-02-20
US5434184A (en) 1995-07-18
FI922424A0 (en) 1992-05-27
ATE128115T1 (en) 1995-10-15
MY136249A (en) 2008-08-29
AP9200385A0 (en) 1992-07-31
US5393779A (en) 1995-02-28
FI922424A (en) 1992-11-29
IL101821A0 (en) 1992-12-30
ZA923356B (en) 1993-03-05
NZ242643A (en) 1994-12-22
CS159292A3 (en) 1992-12-16
JPH05148196A (en) 1993-06-15
SI9200093A (en) 1992-12-31
HU9201609D0 (en) 1992-08-28
IE69043B1 (en) 1996-08-07
PL294704A1 (en) 1993-07-26
EP0516349A2 (en) 1992-12-02
IE921447A1 (en) 1992-12-02
JP3232337B2 (en) 2001-11-26
BR9202002A (en) 1993-01-12
CA2068377A1 (en) 1992-11-29
TW198709B (en) 1993-01-21
DE69204906T2 (en) 1996-02-08
DK0516349T3 (en) 1995-11-06
HU211401B (en) 1995-11-28
GB9111426D0 (en) 1991-07-17
NO922113L (en) 1992-11-30
EP0516349A3 (en) 1993-04-14
GB9210919D0 (en) 1992-07-08
CN1069023A (en) 1993-02-17
RO111569B1 (en) 1996-11-29
ES2076688T3 (en) 1995-11-01
US5480910A (en) 1996-01-02
CN1031564C (en) 1996-04-17
HUT62256A (en) 1993-04-28
YU54592A (en) 1995-10-03

Similar Documents

Publication Publication Date Title
AP301A (en) &#34;4-(2-(2-Hydroxy-2-phenylethylamino) ethoxy)phenylacetic acid,derivatives for use in the treatment of obesity and related conditions.
EP0210849B1 (en) 2-hydroxy-3-phenoxypropyl amines
US5502078A (en) Chemical compounds
EP0591503A1 (en) 4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenylacetic acid as beta 3-adrenoceptor-agonist
EP0516350B1 (en) 2-Hydroxy-2-phenylethylamine derivatives as beta-3-adrenoceptor agonists
EP0565317A1 (en) (2-(2-hydroxy-2 phenylethylamino)ethoxy) phenyl derivatives, processes and intermediates for their preparation, pharmaceutical compositions containing them and their use as Beta-3-adrenoceptor agonists
US5187190A (en) Phenoxypropanolamine compounds
EP0426804B1 (en) 2-(2-hydroxy-3-phenoxypropylamino)-ethoxybenzene derivatives