AU613687B2 - Ethanolamine derivatives - Google Patents
Ethanolamine derivatives Download PDFInfo
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- AU613687B2 AU613687B2 AU26932/88A AU2693288A AU613687B2 AU 613687 B2 AU613687 B2 AU 613687B2 AU 26932/88 A AU26932/88 A AU 26932/88A AU 2693288 A AU2693288 A AU 2693288A AU 613687 B2 AU613687 B2 AU 613687B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/40—Radicals substituted by oxygen atoms
- C07D307/42—Singly bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/56—Radicals substituted by oxygen atoms
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
~hi l r-U -11 1111- COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION NAME ADDRESS OF APPLICANT: Glaxo Group Limited Clarges House 6-12 Clarges Street London W1Y 8DH United Kingdom 613687 NAME(S) OF INVENTOR(S): Ian Frederick SKIDMORE Harry FINCH Alan NAYLOR Lawrence Henry Charles LUNTS Charles WILLBE David MIDDLEMISS ADDRESS FOR SERVICE: DAVIES COLLISON Patent Attorneys 1 Little Collins Stieet, Melbourne, 3000.
COMPLETE SPECIFICATION FOR THE INVENTION ENTITLED: Ethanolamine derivatives The following statement is a full description of this invention, including the best method of performing it known to me/us:i la This invention relates to novel ethanolamine derivative having a stimulant action at P2-adrenoreceptors, to processes for their preparation, to pharmaceutical compositions containing them erd to their use in medicine.
Ethanolamine derivatives have previously been described as bronchodilators having stimulant activity at p-adrenoreceptors.
Thus, for example, UK Patent Specification No. 2140800A describes phenethanolamine compounds of the general structure
RI
CHCH
2
NHC(CH
2
O(CH
2 Ar I2 m n OH R 2 ii in which R I and R 2 each represent hydrogen or C _3alkyl; m is an S integer 2 to 8; n is an integer 1 to 7; and Ar is an optionally I substituted phenyl group.
UK Patent Specification No. 2162842A and European Patent Specification No. 0178919A describes aminophenol compounds of the i general structure i QN!\ I$ J.
ii CHCH 2 NHyXCH 2 CH 2YAr OH R2 ij in which R 1 and R 2 each represented hydrogen of CI-alkyl; N X represents a Ci_ alkylene, C 2 alkenylene ot C2_/ alkynylene chain; *i jY represents e C_ 6 alkylene, C._6 alkenylene or C2.6 alkynylene chain; Ar represents a phenyl group optionally substituted by one or ,ore of a variety of specific substituents; and Q represents a group RI0J-,
R
3 NHCO-, R 3 R4NSOg-, RbSO 2 where R 3 and R 4 each represent a hydrogen atom or a C 1 3 alkyl group, and Rb represents a C 1 4alkyl group.
UK Patent Specification 2165.42A describes dichloroaniline derivatives of the general structure
<*A
i ~I- 2 Cl
\R
\I
H 2N-* HCH 2 NHXCH ,OCH YAr Ci R Cl in which R 1 and R 2 each represent hydrogen or C .alkyl, X reoresents a CIgalkylene, C 2 6 alkenylene or C2- 6 alkynylene chain; Y represents a C _alkylene, C 2 qalkenylene or C2_4alkynylene chain; and Ar represent a phenyl group substituted by one or more of a variety of specific substituents.
We have now found a novel group of compounds which differ I structurally from those of UK Patent Specification Nos. 2140800A, 2162842A and 2165542A, and European Patent Specification No. 0178919A, and which have a desirable and useful profile of activity.
S' Thus the present invention provides compounds of the general formula
R
18
R
I
I I Ar-CHCHNHCXCH2OCH2Y (I) I HH 2 OH R 2 and physiologically acceptable salts and solvates hydrates) thereof, wherein
HOR
3 Ar represents HO-* (where R 3 is a straight or branched C1-3 alkylene group), (b) Rb (where one of R 4 and Rb is a hydroxy group and the other is a hydrogen or halogen atom or a hydroxy group),
HO-.
[where R 6 is a group R'CO-, R7NC 1 R S2- orR52- (where R' and
R
8 each represent a hydrogen atom or a alkyl group and R 9 is a 4 1-3 3 alkyl group) and p is an integer 0 or 1],
R
16
RI/NV
a(d) H (where R 16 and RI/ each repi-.ant a hydrogen atom or a CI-4 alkyl group, or, when R 16 is a hydrogen atom, RI/ may also represent a C alkoxycarbonyl group),
R
0
OCH~
HO-.
(where R 10 is a CI- 3 alkyl group),
H
4 Cl H
C
H
2 C
HO
HO\
OI
HOCH
2
N
CH SO 2
CH
2 H HO-. (j)
NCCH
2 \2
HO-
N 0
H
OH
OH
I I I N 0
H
OH
or t a SI I 1( i t ai t ti l 1 t i at I t t tata t| t i t IE t e X represents a bond or a C,_ alkylene, C2- alkenylene or C2-/ alkynylene chain, Y represents a bond or a C,-6 alkylene, C 2 6 alkenylene or C2 6 alkynylene chain, with the proviso that the sum total of carbon atoms in X and Y is 2 to
R
1 and R 2 each represents a hydrogen atom or a C1_3 alkyl group with the proviso that the sum total of carbon atoms in RI and R2 is not more than A;
R
18 represents hydrogen or CI-. alkyl; Q represents a
R
1 1 4 R12
Z
z II I I
R
11 Ri 2 z group; where 1 Z II I //0 z p 1 T
I
9r 9 o 99 0 5 4e 9 r0 0 99 99 9 9 49 9 99 99 9 9 4* 99 9 9 09 9P 9 0 01 5 Z represents an oxygen or a sulphur atom;
R
1 1 represents a hydrogen or halogen atom or a group C _3 alkyl, nitro, -(CH 2 )tR, -(CH 2 )rCOR 13 or S02NRI 4
R
1 b;
R
12 represents a hydrogen atom or a C_-3 alkyl group, or, when R 1 1 represents a halogen atom, R 1 2 additionally represents a halogen atom; R represents a hydroxy, Ci_3 alkoxy or NR 1 4R15 group:
R
1 3 represents a hydroxy, C1- 4 alk:oxy or NRi'R 1 5 group;
R
1 4 and R 15 each represents a hydrogen atom or i C1-4 alkyl group or
NR
1
'R
1 5 forms a saturated heterocyclic amino group which has 5-7 ring members and optionally contains in the ring one or more atoms selected from or or a group -NH- or -N(CH t represents an integer from 3 to 3; r represents an integer from 0 to 3.
It will be appreciated that the compounds of general formula (I) possess onF or more asymmetric carbon atoms. The compounds according to the invention thus include all enantiomers, diastereoisomers and mixtures thereof, including racemates. Compounds in which the carbon atom in the -CH- group is in the R configuration are preferred.
OH
In the definition of general formula the term alkenylene includes both cis and trans structures.
One preferred class of compounds of formula are those wherein Z is 0. A further preferred class of compounds of formula are those wherein Z is S. Conveniently Q is either II
RI
Z R11 S II
Z
In the general formula the chain X may be for example a bond,
-CH
2
-(CH
2 2
-(CH
2 3
-(CH
2 -CHPC, -(CH2
-(CH
2 2 -CH=CHCH2-, -CH=CH(CH2)2- or -CH2C:CCH 2 The chain Y may be for example a bond, -CH 2
-(CH
2 2
-(CH
2 3
-(CH
2
-(CH
2 5 -CH=CH-, -CEC-, -CH 2 CH=Ct- or CH 2
CC-.
The total number of carbon atoms in the chains X and Y is III II I i 1 ~rPrraau~a~-sc~--r I r t 1 6 preferably 4 to 10 inclusive and may be for example 4, 5, 6, 7, 8 or 9. Conveniently both X and Y are alkylene; X is conveniently a C3 or
C
4 alkylene; it is conveniently a C 1 5 for example C 1 or C 2 alkylene.
R
1
R
2 and R 18 may each be for example hydrogen atoms or methyl, ethyl, propyl or isopropyl groups. If one of R 1 and R 2 is a propyl or isopropyl group, the other is a hydrogen atom or a methyl group. R1,
R
2 and R 18 are each preferably a hydrogen atom or a methyl group. When
R
18 represents a C 1 3 alkyl group, R I and R 2 preferably both represent hydrogen atoms.
A preferred group of compounds is that wherein R 1 8 represents a hydrogen atom.
Another preferred group of compounds is that wherein R 1 and R2 are both hydrogen atoms, or R I is a hydrogen atom and R 2 is a C_- 3 alkyl group, particularly a methyl group, or R I is a methyl group and
R
2 is a methyl group.
Conveniently R 1
R
2 and R 18 are all hydrogen.
In the definition of Ar in compounds of formula R 3 may be, for example, -CH 2
-(CH
2 2- or -(CH 2 3-
CH
3 "Halogen" in the definition of Rb may be for example chlorine or fluorine. R' and R 8 may each be, for example, a hydrogen atom or a methyl, ethyl, propyl or isopropyl group. R 9 may be a methyl, ethyl, propyl or isopropyl group. R 1 0 may be for example a methyl, ethyl or propyl group. R 1 6 and R I 1 may each be for example a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl or t-butyl group. Alternatively, when R 1 6 is a hydrogen atom, R
I
may be for example a methoxycarbonyl or ethoxycarbonyl group.
Ar in compounds of formula may be for example
-U,
HO K, 2 (H22 HO-. HO-.
-7-
HO\H
HO-e
HO
HO-.
(where R 6 is is HCO-, CH 3 CO-, NH 2 CO-, (CH 3
)P'SO
2 7 or CH SO
R
6 NHCH 2 HO-. (where R 6 is as just defined), I I 4 4 I 4144 44 4 4 44 4 4*4 44 4. 4 4 44 4 84 48 4 8 44 44 4 4 44 4 14 14484 R 16 R I'/ HO-* (where R 16 is hydrogen and R 1 7 is methyl),
CH
3 0CH 2
HO
HO-* or a group of type Wi, or The group Ar preferably represents
HOCH
2
HO-.
8- Cl
H
2
N-*
Cl CH 3 SO 2
NH\
or, I; I I l~ I I I I tI I I~ I I I II It I I I I I ii tIll It
HO
When NRIIRI5 in compounds of formula represents a saturated heterocyclic group, this may have 5, 6 or' 7 ring members and optionally contain in the ring a heteroatom selected from 0- or nr a group -NH- or -N(CH 3 Examples of such -NRl'fRI5 groups are pyrrolidino, piperidino, hexamethylenimino, piperazino, N-methylpirierazino, morpholino, homomorpholino or thiamorpholino.
Examples' of the substituents represented by the group R I are hydrogen, chlorine, fluorine or bromine atoms or methyl, ethyl, propyl, -CH 2 OH, -CH 2 N (CH 3) 2
-CH
2
N(CH
2
CH
3 2
-COOCH
3 -COO(CH 2 )2 CH 3
-CONH
2 -CON (C 3) 2' -CON (CH2CH3) 2' CON or -so 2 N (CH 2 CH 3 )2 groups.
The substituent R 12 may be for example a hydrogen atom, or a methyl, ethyl or propyl group or, when R 1 1 ts a halogen atom, R 12 May be for example a chlorine, fluorine or bromine atom.
Particular examples of the group Q when Z is an oxygen atom are those in which RII represents hydrogen, C 1 3 alkyl propyl),
COR~
13 CO 2
CH
3 or CO 2 CH 2 OH or CONRI'fRIb (where R 1 4 and R 1 both represent C 1..
4 alkyl e.g. ethyl groups) and R 12 represents hydrogen, or Q represents the group 0 -9- Alternatively, when Z is a sulphur atom, particular examples of V the group Q are those in which R"I represents hydrogen, chlorine alkyl(e.g. methyl), CONR 14 R' (eg. CONet 2 CH2JH, COR 13 C02CH 3 C0 2 H) or S0 2 NR1 4 RI5 SO 2 NEt) and R 1 2 represents hydrogen, orQ represents the group
S.
Preferred compounds according to the invention include a 1 -[[[6-[[5-(2-furanyl)pentylloxyhexyllaminolmethyl]-4-hydroxy-1,3- Ii benzenedimethanol; N-[5-[2-[[6-[[6-(2-furanyl)hexylloxylhexyllaminoll-l-hydroxyethyij-2hydroxyphenyllmethanesulphonamide; [3 [2-(4-amino)-3 ,5-dichlorophenyl)-2-hydroxyethyl] amino] hexyl] oxylpropyl]-N, N-diethyl-2-furancarboxamide; 4-hydroxy-a I-[[EE6-[E3- (3-thienyl) propoxy Ilhexyll amino] methyl]-1, 3benzenedimethanol; a (benzoE b] thienyl) ethoxyIhexyl amino Imethyl -4-hydroxy-1, 3benzenedimetheaol; 5-[1l-hydroxy-2-[ 4-(2-thienyl) butaxy Ihexyll amino] ethyl]-1, 3- H benzenediol; al-[ [6-[2.-[2-benzo[ bi furanyllethoxy] hexyl] amino] methyll -4-hydroxy-1, 3-benzenedimethanol; (2-benzoE bJ furanyl)butoxyJ hexyl] amino] -1-hydroxye thyl]I- 2 -hydroxyphenylilmethanesulphonamide; 4-Hydroxy-i, '-[[[6-4-(2-thienyl)butxylhe~iyllaminolmethyl]-1,3benzenedirethanol; a I E[ [1 1-d im et hy1-.6 2- (2 th ie nyI) e tho xy Ih e xyIIainno Imeat h y1]-4 hydroxy-l,3, benzenedimethanol; [2 [2-(4-amino-3, 5-dichlorophenyl)-2-hydroxyle thyll amino] hexyl]I o xyIe t h y II- N, N -d ie th y1-2 thiop h en ec arb axam id e; and their physiologically acceptable salts and solvates.
Suitable physiologically acceptable salts of the compounds of general formula include acid addition salts derived from inorganic and organic acids, such as hycrchlorides, hydrobromides, sulphates, phosphates, maleates, tartrates, citrates, benzoates, 4-methoxybenzoates, 2- or 4-hydroxybenzontes, 4-chlorobenzoates, _li ~*IIC-LY~P4LII''LI"L-I 10 p-toluenesulphonates, naphthalenesulphonates, methanesulphonates, sulphamates, ascorbates, salicylates, acetates, diphenylacetates, triphenylacetates, fumarates, succinates, lactates, glutarates, gluconates, tricarballylates, hydroxynaphthalenecarboxylates e.g.
1-hydroxy- or 3-hydroxy-2-naphthalenecarboxylates, or oleates. The compounds may also form salts with suitable bases. Examples of such salts are alkali metal sodium and potassium), alkaline earth metal calcium or magnesium) salts, and salts with organic bases triethylamine).
Salts having a very low solubility in water are particularly convenient where the compolnd is to be administered by inhalation or insufflation. Such salts include diphenyl acetates, 4,4'-methylenebis 3-hydroxy-2-naphthalene carboxylates and 1-hydroxy- and 3-hydroxy-2-naphthalene carboxylates.
The compounds according to the invention have a selective stimulant action at P -adrenoreceptors, which furthermore is of a Si, particularly advantageous profile. The stimulant action was demonstrated in the isolated trachea of the guinea-pig, where compounds were shown to cause relaxation of contractions induced by PGFY or *lc electrical stimulation. Compounds according to the invention have Sshown a particularly long duration of action in these tests.
The compounds according to the invention may be used in the treatment of diseases associated with reversible airways obstruction such as asthma and chronic bronchitis.
The compounds according to the invention may also be used for the treatment of premature labour, depression and congestive heart failure, and are also indicated as useful for the treatment of inflammatory and allergic skin diseases, glaucoma, and in the treatment of conditions in which there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulcsation.
The invention accordingly further provides compounds of formula and their physiologically acceptable salts and solvates for use in the therapy or prophylaxis of diseases associntpd with reversible airways obstruction in human or animal sub ts.
The compounds according to the invention may be formulated for administration in any convenient way. The invention theretore includes within its scope pharmaceutical compositions comprising at -11least one compound of formula or a physiologically acceptable salt or solvate thereof formulated for use in human or veterinary medicine.
Such compositions may be presented for use with physiologically acceptable carriers or excipients, optionally with supplementary medicinal agents.
The compounds may be formulated in a form suitable for administration by inhalation or insufflation, or for oral, buccal, parenteral, topical (including nasal) or rectal administration.
Administration by inhalation or insufflation is preferred.
For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray I presentation from pressurised packs, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichloro- tetrafluoroethane, carbon dioxide or ther suitable gas, or Sfrom a nebuliser. In the case of a pressurised aerosol the dosage I unit may be determined by providing a valve to deliver a metered j amount.
Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a
S'
l suitable powder base such as lactose or starch. The powde: composition may be presented in unit dosage form in for example Scapsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.
For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, j syrups or suspensions prepared by conventional means with acceptable excipients.
For buccal administration the composition may take the form of tablets, drops or lozenges formulated in conventional manner.
The compounds of the invention may o, f-rmulated for parenteral administration by bolus injection or continuous infusion.
Formulations for injection may be presented in unit dosage form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
T 12 Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
For topical administration the pharmaceutical composition may take the form of ointments, lotions or creams formulated in a conventional manner, with for example an aqueous or oily base, generally with the addition of suitable thickening agents and/or solvents. For nasal application, the composition may take the form of a spray, formulated for example as an aqueous solution or suspension or as an aerosol with the use of a suitable propellant.
The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g.
containing conventional suppository bases such as cocoa butter or other glyceride.
SWhere pharmaceutical compositions are described above for oral, buccal, rectal or topical administration, these may be presented in a conventional manner associated with controlled release forms.
A proposed daily dosage of active compound for the treatment of man is 0.005mg to 100mg, which may be conveniently administered in one
S
f or two doses. The precise dose employed will of course depend on the age and condition of the patient and on the route of administration.
Thus a suitable dose for administration by inhalation is 0.005mg to for oral administration is 0.02mg to 100mg, and for parenteral administration is O.Olmg to 2mg for administration by bolus injection and O.Olmg to 25mg for administration by infusion.
In the following description relating to the preparation of compounds of formula and intermediates used in the preparation thereof, X, Y, Ar, R 1
R
2
R
18 and Q are as defined for general formula unless otherwise specified. Any hydroxy and/or amino groups present in the starting materials may need to be in a protected form and the final, step may be the removal of a protecting group.
Suitable protect;ing groups and methods for their removal are for example those described in "Protective Groups in Organic Chemistry", Ed. 3.F.W. McOmie (Plenum Press, 1973), and "Protective Groups in Organic Synthesis", by Theodora Greene (John Wiley and Sons Inc, 1981). Thus hydroxyl groups may for example be protected by aralkyl groups such as benzyl, diphanylmethyl or triphenylmet"yl, or as tetrahyropyranyl derivatives. Suitable amino prrtecting groups 3 13 include aralkyl groups such as benzyl, a-methylbenzyl, diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl. Conventional methods of deprotection may be used.
Thus for example aralkyl groups may be removed by hydrogenolysis in the presence of a metal catalyst palladium on charcoal).
Tetrahydropyranyl groups may be cleaved by hydrolysis under acidic conditions. Acyl groups may be removed by hydrolysis with a base such as sodium hydroxide or potassium carbonate, or a group such as trichloroacetyl may be removed by reduction with, for example, zinc and acetic acid.
In one general process a compound of general formula may be prepared by alkylation, using conventional alkylation procedures.
SThus, for example, in one prouess a compound of general formula in which R I is a hydrogen atom may be prepared by t alkylation of an amine of general formula (II) oft* Ar---CHCHNH 2
(II)
OH
followed where necessary by removal of any protecting groups.
The alkylation may be effected using an alkylating agent of general formula (III): LjHXCH 2 0CCH YQ (III)
R
2 (wherein L represents a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or a hydrocarbylsulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyloxy).
The alkylation is preferably effected in the presence of a suitable acid scavenger, for example, inorganic bases such as sodium or potassium carbonate, organic bases such as triethylamine, diisopropylethylarnine or pyridine, or alkylene oxides such as ethylene oxide or propylene oxide. The reaction is conveniently 14 effected in a solvent such as acetonitrile or an ether e.g.
tetrahydrofuran or dioxan, a ketone e.g. butanone or methyl isobutyl ketone, a substituted amide e.g. dimethylformamide or a chlorinated hydrocarbon e.g. chloroform at a temperature between ambient and the reflux temperature of the solvent.
According to another example of an alkylation process, a compound of general formula in which RI represents a hydrogen atom may be prepared by alkylation of an amine of general formula (II) with a compound of general formula (IV):
R
2
COXCH
2
OCH
2 YQ (IV) in the presence of a reducing agent, followed where necessary by removal of any protecting groups.
Suitable reducing agents, when Z is an oxygen atom, include hydrogen in the presence of a catalyst such as platinum, platinum J oxide, palladium, Raney nickel or rhodium, on a support such as charcoal, using an alcohol, e.g. ethanol or an ester e.g. ethyl acetate or an ether e.g. tetrahydrofuran, or water, as reaction solvent, or a mixture of solvents, e.g. a mixture of two or more of those just described at normal- or elevated temperature and pressure, for example for 20 to 1000C and from 1 to 10 atmospheres.
i Alternatively, when Z is an oxygen or sulphur atom, the reducing agent may be a a hydride such as diborane or a metal hydride such as sodium borohydride, sodium cyanoborohydride or lithium aluminium hydride.
Suitable solvents for the reaction with these reducing agents will depend on the particular hydride used, but will include alcohols such as methanol or ethanol, or ethers such as diethyl ether or tert-butyl methyl ether, or tetrahydrofuran.
Alkylation of an amine (II) with a compound of formula (IV) may result in formation of the intermediate imine of formula (V)
R
1 8 Ar- HCHN=TXCH 2 OC 2YQ (V) OH R 2 15 Reduction of the imine using the conditions described above, gives a compound of general formula In another general process a compound of general formula (I) may be prepared by reduction. Thus, for example, a compound of general formula may be prepared by reducing an intermediate of I general formula (VI):
RI
8
R
1 I I Ar-X -CHNHCXCHO2CH 2 YQ (VI)
R
2 (wherein X I represents a reducible group and/or Ar and/or Q contains a S. reducible group and the other(s) take the appropriate meaning as follows, which is X 1 is -CH(OH)- and Ar and Q are as defined in formula followed where necessary by removal of any protecting groups.
,Suitable reducible groups include those wherein X I is a group and Ar contains a substituent -CHO or -CO 2
R
19 (where R 19 Srepresents a hydrogen atom or an alkyl C 1 -3 alkyl) group).
S The reduction may be effected using reducing agents conveniently employed for the reduction of carboxylic acids, aldehydes, esters and Sketones.
Thus for example when X i in general formula (VI) represents a 4 >C=O group and/or Ar contains a substituent -CHO or -CO 2
R
1 9 this may be reduced to a -CH(OH)- or -CH 2 0H group respectively using for :I ,example, a complex metal hydride such as lithium aluminium hydride.
The reaction may be effected in a solvent such as an ether e.g.
diethyl ether or tetrahydrofuran, or a halogenated hydrocarbon e.g.
j dichloromethane, at a temperature of OC to the reflux temperature of Sthe solvent. Alternatively, when Z is an oxygen atom and X represents the group this may be reduced to a -CH(OH)- group using hydrogen in the presence of a catalyst as previously described for process (1) part Compounds of formula may also be prepared by a process comprising interconversion of one compound of formula into another.
-7 1 L 16 Thus for example a compound of formula in which R 11 represents the group -(CH 2 )rCOR i where R 1 3 is hydroxy may be prepared by hydrolysis of the corresponding compound in which R 13 represents CI_ 4 alkoxy. The hydrolysis may for example be carried out under basic conditions using e.g. sodium hydroxide.
According to a further example of an interconversion process, a compund of formula in which R 1 represents -(CH 2 )tNR '4R b may be prepared by reducing the corresponding compound of formula in which R 1 1 represents -(CH 2 )rCONR 1RIb wherein r represents zero, 1 or 2. The reduction may be carried using for example a hydride reducing agent e.g. lithium aluminium hydride, in the presence of a suitable solvent, for example, an eter such as diethyl ether or tetrahydrofuran.
In the general processes described above, a compound of formula obtained may be in the form of a salt, conveniently in the form of a physiologically acceptable salt. Where desired, such salts may be e i converted to the corresponding free acids using conventional methods.
Physiologically acceptable salts of the compounds of general formula may be prepared by reacting a compound of general formula i* with an appropriate acid or base in the presence of a suitable i solvent such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol, e.g. methanol, ethanol or iso-propanol.
S, Physiologically acceptable salts may also be prepared from other salts, including other physiologically acceptable salts, of the compounds of general formula using conventional methods.
When a specific enantiomer of a compound of general formula (I) is required, this may be obtained by resolution of a corresponding racemate of a compound of general formula using conventional methods.
Thus, in one example an appropriate optically active acid may be used to form salts with the racemate of a compound of general formula The resulting mixture of isomeric salts may be separated for example by fractional crystallisation, into the diastereoisomeric salts from which the required enantiomer of a compound of general formula may be isolated by conversion into the required free base.
Alternatively, enantiomers of a compound of general formula (I) may be synthesised from the appropriate optically active intermediates T~ 17 using any of the general processes described herein.
Specific diastereoisomers of a compound of formula may be obtained by conventional methods for exaiple, by synthesis from an appropriate asymmetric starting material using any of the processes described herein, or by conversion of a mixture of isomers of a compound of general formula into appropriate diastereoisomeric derivatives e.g. salts which then can be separated by conventional means e.g. by fractional crystallisation.
The int rmediate compounds of general formula (VI) in which X
I
represents a group >C=O may be prepared from a haloketone of formula
(VII):
R
1 8 Ar-COCHHal (VII) S(where Hal represents a halogen atom, and any hydroxyl and/or amino group(s) in the group Ar may optionally be protected) by reaction with Ir an amine of general formula (VIII)
R
2 0 NHCXCH20CH2YQ (VIII)
S
R 2 (wherein R 2 0 is a hydrogen atom or, when Z is an oxygen atom, a group convertible thereto by catalytic hydrogenation).
The reaction may be effected in a cold or hot solvent, for example dimethylformamide, an ester such as ethyl acetate, or an ether such as tetrahydrofuran in the presence of a base such as diisopropylethylamine.
The amines of ;ormula (II) and haloketrnes of formula (VII) are either known compounds or may be prepared by methods analogous to those used for the preparation of the known compounds.
Intermediates of formulae (III), (IV) and (VIII) may be prepared by methods analogous to those used for the preparation of known compounds. Suitable methods include those described in UK Patent Specification No. 2140800A and in the cxemplification included hereinafter.
The following examples illustrate the invention. Temperatures are in 'Dried' refers to drying using magnesium sulphate or sodium sulphate except where otherwise stated. Thin layer chromatography was carried out over SiO 2 Flash column chromatography (FCC) 8 was carried out on silica (Merck 9385) using, unless otherwise stated, one of the following solvent systems: A-toluene:ethanol: 0.88 ammonia; B-ethyl acetate:methanol:triethylamine; C-toluene:ethanol:triethylamine; D-ethyl acetate:methanol:0.88 ammonia. The following abbreviations are used: THF tetrahydrofuran; DMF dimethylformamide; BTPC bis(triphenylphosphine)palladium (II) chloride; DEA N,N-diisopropylethylamine; TAB tetra-n-butylammonium bisulphate.
i Intermediate 1 referred to below is al-(aminomethyl)-4-hydroxy-l,- 3-benzenedimethanol.
SIntermediate 2 S 2-2-[(6-Bromohexyl)oxy]ethyl]furan t" 2-Furanethanol (2g) in DMF (5ml) was added dropwise to a suspension of it .sodium hydride (0.43g) in DMF (20ml). The mixture was stirred for and added dropwise to 1,6-dibromohexane (21.8g). The resulting suspension was heated at 60-70 0 for 18h, poured into water (200ml) and extracted with diethyl ether (3x100ml). The dried extract was ,evaporated and the residue was purified on a column of silica eluted with cyclohexane. The resulting oil was fractionally distilled S(Kugelrohr) to give the title compound as a colourless oil (1.7g) b.p.
75-800/0.3 Torr.
Intermediate 3 5-Propyl-2-furanethanol A solution of n-butyllithium in hexane (1.55M, 100ml) was added over min to a stirred solution of furan (lOg) and tetramethylethylenediamine (17.4g) in dry THF (100ml) at 00 under nitrogen. The mixture was stirred for 2h at 00, treated with iodopropane (25g) over 15 min at 00 (reaction exothermic), and stirred at 00 for lh and at 230 for lh. The mixture was cooled to 00, nbutyllithium (1.55M, lOOml) was added over 10min and the mixture stirred at 00 for a further lh. The mixture was cooled to -100, treated with a solution of ethylene, oxide (7g) in dry THF (20ml) over and stirred at -100 to 00 for 2h and at 230 for 18h. Water 19 (200ml) was added, the organic solvents removed in vacuo and the residue extracted with ether (3x200ml). The extracts were washed with hydrochloric acid (20Cml), 8% sodium bicarbonate (50ml) and brine dried and evaporated in vacuo to give a brown oil which was distilled (Kugelrohr) to give the title compound as a pale-yellow oil (18.2g) b.p. 191-200 0 Intermediate 4 2-[[2-(6-Bromohexyl)oxy]ethyll-5-propylfuran A mixture of Intermediate 3 1,6- dibromohexane (14.5g), TAB (0.35g) and 50% aqueous sodium hydroxide (15ml) was vigorously stirred at 230 un.er nitrogen for 7h. 'ne mixture was diluted with water extracted with ether (2 x 50ml) and the extracts were washed with water (50ml) ahd brine (50ml), dried and evaporated in vacuo to "give a yellow oil. Distillation (Kugelrohr) afforded the title compound as a pale-yellow oil (5.36g) b.p. 192-1980/3 Torr.
Intermediate 2-[[5-(6-Bromohexyl)oxy]pentyl]furan A mixture of 1,6-dibromohexane 2-furanpentanol TAB (0.25g) and 50% aqueous sodium hydroxide (30ml) was vigorously stirred at 230 for 17h, diluted with water (150ml) and extracted with ether (2 x 50ml). The extracts were washed consecutively with water and brine (50ml), dried and evaporated in vacuo to give a pale-yellow Soil (10.0g) which was purified by FCC eluting firstly with cyclohexane (to remove excess dibromohexane) and then with cyclohexane-ethyl acetate The product (3.7g) was distilled (Kugelrohr) to afford the title compound as a colourless oil (3.4g) b.p. 160-170/0.1 Torr.
Intermediate 6 2-[2-[(5-Bromopentyl)oxy]ethyl]benzo(b)furan A mixture of 2-benzo(b)furanethanol (2.00g), 1,5-dibromopentane sodium hydroxide (7ml) and TAB (0.2g) was vigorously stirred at 240 for 21h, then partitioned between water (50mA) and ether The organic phase was washed with brine (50mi), dried and evaporated in vacuo. The oily residue was purified by FCC eluting with
I
20 hexane-diethyl ether (97:3) to give the title compound as a colourless oil (2-70g), t.l.c. (hexane diethyl ether 4:1) Rf 0.54.
Intermediate 7 (6-Bromohexyl) oxyl ethyl] benzo[ b] furan The title compound, as a colourless oil (2.75 t.l.c. (diethyl ether) Rf 0.61, was prepared from 2-benzo[blfuranethanol (2.00g) and l,6-dibrc.-iohexane (7mZ) by the method described in Intermediate 6, except that hexane-diethyl ether (9:1 then 1:1) was used as the FCC eluent.
-Intermediate 8 .2-113-[(6-Bromohex yl)ox ylpropy lifuran The title compound, as a colourless oil t.l.c.
(cyclohexane-diethyl ether 3:1) Rf 0.6, was prepared from 2-furanpropanol (2.0g) and 1,6-dibromohexane (12.2g) by the method described in Intermediate 6, except that cyclohexane followed by cyclohexane-diethyl ether was used as the FCC eluent.
Intermediate 9 Methyl (6-bromohexyl) oxy -1-butynyl] -2-f urancarboxy late Nitrogen gas was bubbled through a solution of methyl 5-bromo-2furancarboxylate (2.34g), 4-[(6-bromohexyl)oxy] -1-butyne (2.34g) and dicyclohexylamine (2.26g) in acetonitrile (30m.Z) for 15 min.
BTPC (84mg) and copper iodide (15mg) were added and the mixture was refluxed under nitrogen for 3h, diluted with ether (200m~z), filtered and the filtrate evaporated in vacuo. The resulting brown oil was purified by FCC eluting with cyclohexane-diethyl ether (10:1) to give the title compound as a brown oil (2.51g), t.l.c.
(hexane-ether 10:1) Rf 0.21.
Intermediate Methyl (5-broropentyl)oxy-l-propynylj-2-furancarboxylate Methyl 5-bromo-2-furancarboxylate (1 .49g) was treated with (1.49g) according to the method of r UUgUI 21 Intermediate 9 to give the title compound as a yellow oil (0.97g), t.l.c. (cyclohexane-diethyl ether 10:1) Rf 0.18.
Intermediate 11 5-[3-[(6-Bromohexyl)oxy]-1-propynyl]-NN-diethyl-2-furancarboxamide 5-Bromo-N,N-diethyl-2-furancarboxamide (2.0g) was treated with 3-[(6-bromohexyl)oxy]-l-propyne (1.87g) according to the method of Intermediate 9 except that the reaction mixture was stirred under nitrogen at 600 for 4h, and hexane-ether (5:1 then 2:1 then 1:1) was used as the eluant for FCC. This afforded the title compound as a dark yellow oil (2.98g), t.l.c. (diethyl ether) Rf 0.35.
Intermediate 12 5-[3-[(6-Bromohexyl)oxy]propyl]-N,N-diethyl-2-furancarboxamide S. A solution of Intermediate 11 (2.98g) in ethanol (50m.) was added to T"'S pre-hydrogenated 10% palladium on charcoal (50% aqueous paste, l.lg) So, in ethanol (50mA) and hydrogenated. The mixture was filtered through hyflo and evaporated in vacuo and the oily residue taken up in dichloromethane (30ml), filtered again and evaporated in vacuo to afford the title compound as a brown oil (2.70g), t.l.c. (diethyl ether) Rf 0.37.
Intermediate 13 Methyl 5-[4-[(6-bromohexyl)oxy]butyl]-2-furancarboxylate A solution of Intermediate 9 (2.35g) in methanol (100ml) and charcoal were refluxed on a steam bath for 15 min, filtered and the filtrate evaporated in vacuo to give a brown oil (2.35g). A solution of the oil in methanol (100mZ) was hydrogenated over pre-reduced palladium oxide on charcoal (50% aqueous paste, 600mg) in methanol The mixture was filtered through hyflo and evaporated in vacuo to give the title compound as a yellow oil t.l.c.
(hexane-ether 9:1) Rf 0.16.
Intermediate 14 Methyl 5-[3-[(5-bromopentyl)oxy]propyl]-2-furancarboxylate 22 Intermediate 10 (0.9g) in methanol (50mi) was treated with charcoal (ca 0.5g) and subsequently hydrogenated according to the method of Intermediate 13. Purification of the initial product by FCC eluting with cyclohexane-ether (10:1) gave the title compound as a colourless oil (0.37g), t.l.c. (cyclohexane-ether 10:1) Rf 0.12.
Intermediate (6-Bromohexyl)oxy]butyl]-2-furanmethanol A solution of Intermediate 13 (1.0g) in diethyl ether (1OmZ) was added dropwise to a stirred suspension of lithium aluminium hydride (0.15g) in diethyl ether (5mZ) at room temperature under nitrogen. The mixture was stirred at room temperature for 0.5h and then carefully quenched successively with water (0.2mA), 2N sodium hydroxide (0.2mA) and water (0.6mi). The mixture was diluted with diethyl ether (100mA), filtered through hyflo and evaporated in vacuo to give an Soil. Purification by FCC eluting with hexane-ether gave the title compound as a colourless oil (0.82g), t.l.c. (hexane ether 1:1) Rf 0.17.
ii I i| Intermediate 16 referred to below is 4-amino-a-(aminomethyl)-3,5dichlorobenzenemethanol.
SIntermediate 17 6-(2-Furyl)-5-hexenol 6-(2-Furyl)-5-hexenoic acid (3.6g) in ether (25ml) was reduced according to the method of Intermediate 15, except that the reaction time was 1.5h, and there was no purification by FCC. The title compound was obtained as a pale yellow oil (2.89g), t.l.c.
(hexane-ether 1:1) Rf 0.17.
Intermediate 18 2-Furanhexanol A solution of Intermediate 17 (2.84g) in ethanol (18ml) was hydrogenated according to the method of Intermediate 12. The mixture was filtered through hyflo and evaporated in vacuo to afford a pale yellow oil (2.78g), which was purified by FCC with ether eluent to F- I 23 give the title compound as a colourless oil (2.25g), t.l.c. (ether) Rf 0.39.
Intermediate 19 2-[6-[(6-Bromohexyl)oxy]hexyl]furan A mixture of Intermediate 18 (1.52g), 1,6-dibromohexane (4ml), sodium hydroxide solution (4ml) and TAB (100mg) was vigorously stirred for 22h, diluted with water (25ml) and extracted with ether The organic phase was dried and evaporated in vacuo. The residue was purified by FCC eluting with hexane followed by hexane-ether (19:1, 9:1) to afford the title compound as a colourless liquid (2.00g), t.l.c. (hexane-ether 5:1) Rf 0.39.
Intermediate 6-[(6-Bromohexyl)oxy]-l-hexyne (5g) was treated according to the method of Intermediate 1 except that the reactants were stirred under nitrogen. FCC elution ith hexane followed by hexane:ether (95:5) gave the title compound as a colourless oil. t.l.c. (hexane:ether 2:1) Rf 0.80.
Intermediate 21 Methyl 5-[6-[(6-bromohexyl)oxy]-l-hexynyl]-2-furancarboxylate Methyl 5-bromofuran-carboxylate (5.4g) was treated with Intermediate (6.88g) according to the method of Intermediate 9 except that the reaction mixture was refluxed under nitrogen for 2h. Purification by FCC eluting with hexane:ether gave the title compound as a colourless oil t.l.c. (hexane:ether 9:1) Rf 0.15.
Intermediate 22 Methyl 5-[6-[(6-bromohexyl)oxy]hexyl]-2-furancarboxylate A mixture of Intermediate 21 (6.0g) and charcoal (ca. Ig) in ethanol (100ml) was refluxed on a steam bath for 15mins, filtered and the filtrate evaporated in vacuo. A solution of the residual oil in ethanol (150ml) was hydrogenated over pre-reduced 10% palladium oxide on charcoal (50% aqueous paste, lg)ccatalyst. The mixture was filtered through hyflo and the filtrate was evaporated in v\cuo to I1 44 1 4 44 44 44 44 4 4 4 4444 44 44 4 4 44 44 4 *444 44 4 44 ~4 *4 4 4* 4 4 4 44 4 44 L 4 44 L 44 E4*4~ 4 4444.4 44444 A 4 24 give an orange oi.l. Purification by FCC eluting with hexane-ether (7:l45;1) gave the title compound as a colourless oil (5.17g), t.l.c.
(hexane, Athe~r 5:1) Rf 0.28.
Intermediate 23 N, N-Diethyl-5-[6-[ (6-bromohexyl) ox ]-1-hexynyll-2-f uancarboxamide N,N -diethyl-5 -brom o-2 -f urancarbox amidea (1.5g) was treated with (6-brumohexyl)oxy-l-hexyne 59g) and N, N-oicyclohexylamine (2-10g) according to the method of Intermediate 9 except that the reaction mixture was reflux.-d under iitrogen for, 3h and FCC eluting with hexene "'ollowed by hexane:ether gave the ttle compound as an orange oil1 (1.90g), t.l.c. (hexane:ether 1:1l) Rf 0.15.
Tntermediate 24 N_,N-Diethyl-5-[6-[ (6-bromohexyl)oxylhexyl]-,2-furancrbxamide Intermediate 23 (1.9g) wsias treated according to the method f Intermediate 22 excluding the purification step. The title compound was obtained as an orange oil (3-84g) t.l.c. (System A 40:10:1) Rf 0.68.
Intermediate (6-Bromohexyl)oxylbutyllbenzo[blfuran A mixture of 2-benizo[bjfurnbutnoJ, 1,6--dibromohexane (7.7ml), TAB (500mg) in '50% W/v sodium hydroxide solution (100mZ) was stirred at room temperature overnigh~t. Water (100ml) was added and the mixture extracted with ethyl acetate (2xlOOml). The combi.ried organic extracts were dried and concootr~ted to give an oil.
'Purification by FCC eluting with hexane:ethyl acetate, l00:0-*95:5) gave the title compound as a clear oil t.l.c. (ether) Rf 0.83.
Inte-rmediate 26 (6-Bromohe'xyl) oxy] butyl] thiophene A mixture of 1,6-dibromohexane 2-thiophenebu.tanol Og) TAB (0.25o' and 50% aqueous NaOH (8m1) was vigorously stirred at 23 0 for 15h. The ii ,,xture was diluted with water (50m extracted with diethyl ether (2 x 50m1) -ihd the extracts washed with water '(50m1), and brine dried and evaporated in vacuo to give a yellow oil (11g). Purification by FCC on silica eluting with cyclohexane and then cyclohexane-ethyl acetate afforded a product (5.2g) which was distilled in vacuo to give the title compound as a colourless oil (3.6g) b-p.
185-1l050/0.8 torr. T.l.c. (ethyl acetate-cyclohexane 1:4) Rf 0.73.
Intermediate 27 5-Methyl-2-thienylpropanol N-Butyllithium in hexane (1.5M; 35.6ml) qas added dropwise at room temperature under nitrogen to a solution of 2-methyithiophene in dry THF (50m1). After stirrt.ng for 2.25h, oxetane (4.42g) in dry THF (15m1) was added drepwize and stirring continued for 22.5h.
Saturated ammonium clilaride soluv .,on (200m1) was added and the mixture extracted with diethyl ether (3x20,..vl), dried and evaporated in vacua to give an oil. Purification by FCC on silica gel with cyclohexane-diethyl ether as eluent gave the title compound as a pale orange oil T.l.c. (cyclohexane-diethyl ether 1:1) Rf 0.31.
Intermediate 28 A mrixture of Intermediate 27 1,6-dibromohexane (3m1), TAB (0.39) and aqueous sodium hydroxide solution (50' w/v, l0ml) was stirred at room tempaP~ture for 19h. The resulting emulsion was treated with water (5Oinl), extracted with ether (2xlOOml; 50ml) and the combined extracts were dried and evaporated in vacua to give a yellow liquid Purification by FCC on silica gel using cyclchexal~ie-diethyl ether as eluent gave the title compound as a pale yellow oil T-l-c. (cyclohexane-.diethyl ether 1:1) Rf 0.66.
Intermediate 29 A mixture of 2-(2-thienyl)ethanol 1,5-dibromopentane (23.0g), aqueous sodium hydroxide (50% w/v; 25m1), and TAB (0.25g) was stirred at room temperature for 18h, dilute i with water (50m1), and extracted hh.- I 26 with diethyl ether (2xl00ml). The dried extract was evaporated and the residue was purified by FCC eluting with cyclohexane followed by cyclohexane-diethyl ether to give the title compound as a colourless oil T.l.c. (cyclohexdne-diethyl ether 3:1) Rf Intermediate 2,2-Dimethyl-7-[2-(2-thienyl)ethoxy]heptanoic acid n-Butyllithium in hexane (1.6M; 27.5ml) was added dropwise to diisopropylamine (4.4g) in THF (10ml) at -78 0 under nitrogen. The mixture was warmed to 00, stirred for 40 min, and isobutyric acid (1.94g) was added dropwise. The resulting suspension was stirred at room temperature for 4h and Intermediate 29 (4.0g) wjis added dropwise.
The mixture was stirred for 16h at room teinpereture, treated with ^hydrochloric acid (2M; 50ml), and extracted with diethyl ether (2xl00ml). Tne dried extract was evaporated and the residue was 4 I purified by FCC eluting with cyclohexane-diethyl ether to give *4 the title compound as a colourless oil T.l.c.
(cyclohexane-diethyl ether 3:1) Rf 0.2.
t M, Intermediate 31 t $1 i, -Dimethyl-6-[2-(2-thienyl)ethoxy]hexanamine t' Ethyl chloroformate (1.2g) in acetone (5ml) was added to a solution of Intermediate 30 (2.84g) and triethylamine (1.1g) in acetone (30ml) and water at 00. The mixture was stirred ("or 30 min at 00 and sodium azide (0.72g) in water (10ml) was added dropwise. The resulting suspension was stirred at room temperature for lh, diluted with water (50ml), and extracted with toluene (2x100ml). The dried extract was evaporated during 2h at ca 75 0 /30mmHg and the resulting isocyanate in tert-butanol (50ml) was refluxed for 18h. Tert- butanol was removed under reduced pressure and the residue was treated with trifluoroacetic acid (20ml). The solution wi s stirred at room temperature for ih and trifluoroacetic acid was removed under reduced pressure. The residue was basified with aqueous sodium hydroxide (2M) and extracted with diethyl ether (2xlOOml). The dried extract was 04 4 o 44 4 04 44 4* 4$ o 4 4444 44 44 4 0 44 44 4 4444 44 4 4 41 4 44 4 44 4 04 4 44 44 4 44 4 4 4 4~ 4 4 4~ 44 4444 4~44t~ 27 evaporated to give the title compound as a pale yellow oil (2.1g).
T-l-c. (cyclohexane--diethyl ether 3:1) Rf 0.1.
Intermediate 32 (2-Thienyl.)ethoxyll-2-heptanone A solution of Intermediate 29 (3.0g) in diethyl ether (i5ml) was added dropwise to magnesium (0.25g). The mixture was stirred For 1h and added dropwise during 90mmn trn acetic anhydride (2.25g) in diethyl ether (l0mi) at -7E 0 Thwe resulting suspension was stirred for lh at -780, warmed to -10t', treated with saturated aqueous ammonium chloride (30m1), and extracted with diethyl ether (2x50m1). The diethyl ether extract was washed with aqueous sodium hydroxide (2M; 50m1), water and brine (50m1), dried and evaporated. The residue w~is purified by FCC eluting with cyclohexane-diethyl ether to' .give the title compound as a colourless oil T.l.c.
(cyclohexane-diethyl ether 3:1) Rf 0.25.
Intermediate 33 (6-Bromohexyl)oxy ]ethyl] benzo[blthiophene 2-Benzo[,blthiopheneethanol (2.20g), 1,6-dibromohexane (2.59m1), TAB (0.25g), aqueous 12-5M sodium hydroxide (9m1), and ether (20m1) were stirred overnight at. room tenperature. The mixture was diluted with water (50m1), extracted with ether (3x50m1), and the combined, dried extracts were evaporated. The residual oil was purified by FCC eluting with cyclohexane-diethyl ether (100:0+98:2) to give the title compound as a colourless oil (2.73g).
Analysis Found C,56.55;H,6.3;Br,23.8;S,9.4.
C
1 6
H
21 BrOS requires C,56.3;H,6.2;Br,23.4;S,9.4%1.
Intermediate 34 (6-Bromohexyl)oxylpropyllthiophene A mixture of 2-thiophenepropanol 1,6-dibromohexane (25g), 50%1 aqueous sodium hydroxide (25m.Z) and TAB (500mg) was stirred at room temperature overnight. Water (lO0mZ) was added and the mixture was extracted with ether (2xl00m1). The organic layer was dried and concentrated to en oil which was pufified by FCC eluting with hexane OH R 2 28 to give the title compound as a colourless oil T.l.c.
(hexane-diethyl ether 9:1) Rf 0.50.
Intermediate 5-[3-[(6-Bromohexyl)oxy]propyl]-2-thiophenecarboxylic acid Butyl lithium (1.6M in hexane, 19.5mi) was added to a stirred solution of Intermediate 34 (9.5g) in dry THF (100mZ) at -780 under nitrogen.
The yellow solution was stirred for 30 min then added slowly to a stirred slurry of dry ice (~100g) in dry THF (100mi) at -780 under nitrogen. After the addition the reaction mixture was slowly brought to room temperature, stirred for lh then treated with 2N hydrochloric acid (100mA). The THF was evaporated and the aqueous residue was extracted with ether (2xlOOm£). The organic extracts were dried and concentrated to an orange semi-solid which was triturated with boiling S" hexane to give the title compound as a pale brown solid (7.1g) m.p.
93-950.
I t' Intermediate 36 Propyl 5-[3-[(6-bromohexyl)oxy]propyl]-2-thiophenecarboxylate A mixture of Intermediate 35 N,N-dicyclohexylcarbodiimide (4.15g), 4-(dimethylamino)pyridine (300mg) and propanol (2.4g) in dichloromethane (50ml) was stirred at room temperature for 4h. Ether (150mz) was added, the precipitate was filtered off, the solvent was evaporated and the residual oil was purified by FCC eluting with cyclohexane-diethyl ether (19:1) to give the title compound as a yellow oil T.l.c. (hexane-diethyl ether 9:1) Rf 0.19.
Intermediate 37 3-[3-[(6-Bromohexyl)oxy]propyllthiophene 3-Thiophenepropanol (5g) was treated according to the method of Intermediate 34 to give the title compound as a colourless oil (5.8g).
T.l.c. (hexane-diethyl ether 9:1) Rf 0.42.
Intermediate 38 2-[3-[(6-Bromohexyl)oxy]propyl]-5-chlorothiophene -29- Butyl lith'iJm (1.6M in hexane, 10.2mYZ) was added to a stirred solution of Intermediate 3.4 (5.0g) in dry THF (5OmZ) at 780 under nitrogen.
The yehlow solution was stirred at -780 for 30 min, a solutioi of hexac hioroe than e (3g) in dry THF (19mlZ) was added and the reaction mixture oas stirreC; for 15 min at -780. Saturated aqueous ammonium c;1.ori, e (25ml) was added, the mixture was warmed to room temperature, the phases were separated and the orgnanic layer was dried and concentrated to an .range oil, which was purified by FCC eluting with toluene-hexane io 'give the title compound as a pale yellow oil T.l.c. (hexane-diethyl ether 9:1) Rf 0.42.
Inter:ediate 39 H 2-[2-[(6-Bromohexyl)oxylethyllthiophene A mixture of 2-thienylethanol (10.0g), 1,6-dibromohexane (57.10g) and TAB (1.3g) in 40%0 sodium hydroxide solution (40mY.) was stirred vigorously under nitrogen at r~om temperature for 5h. The mixture was diluted with water (400mZ) and extracted with diethyl ether (2x300myZ), dried and evaporated in vacuo to give an oil. Purification by FCC eluting with hexane-ether (100:0+95:5) gave the title compound as a colourless oJl (i9.28g), t.l.c. (hexane-ether 9:1) Rf 0,39.
Intermediate (6-Bromohexyl)oxylethyl-2-thiophenecarboxyli acid n-Butyllithium in hexane (1.55M, 22.2m.) was tadded to a stirred solution of 2-[2-[(6-bromohexyl) oxy ethyl] thiophene (10.Og) and II treated according to the method of H Intermediate 15, except that the reaction mixture was brought to rom temperature very slowly over 3.5h. The combined organic extracts were dried and evaporated in vacuo to give a pink bolid, which on recrystallisation from ether-hexane gave the title compound as a pale-pink solid (8.j34g) m.p. 60-610.
I termediate 41 (6-Bromohexyl) oxy Iethyl I-2-N N- diethyl thiophenecarboxamide Tsobutyl chloroformate (1.22g) in acetonitrile (5ml) was added dropwise over 5 min to a stirred solution of Tntermediate 40 (2.5g) -j 88 8 48 8t 4888 88 8 #r 88( #8 88 8 4 88 8 88l 888 8~ 88 81t 8tl 30 triethylamine (7.5mA) and acetonitrile (15mi) at OOC. After 30 min diethylamine (2.32mi) was added and the solution stirred for a further 2h, diluted with ether (50ml) and filtered. The filtrate was evaporated in vacuo to give a brown oily solid, which was triturated with ether-hexane (ca 1:1) to give a solid and a brown oil. The oil was purified by FCC eluting with hexane ether ethyl acetate to give the title compound as a colourless oil (0.60g), t.l.c. (ether) Rf 0.67.
Intermediate 42 Methyl 5-[2-[(6-bromohexyl)oxy]ethyl]-2-thiophenecarboxylate A solution of Intermediate 40 (3.25g) in methanol (20ml) containing concentrated sulphuric acid (2mL) was stirred at reflux for 4h. The solution was allowed to cool and then basified to pH 8, initially using 2N sodium hydroxide solution and then 8% sodium bicarbonate solution. The methanol was evaoorated in vacuo and the residue extracted with ether (3)150mi). The combined organic phases were washed successively with brine (lOml), water (100m), dried and evaporated in vacuo to give the title compound as a brown oil (3.16g), t.l.c. (ether) Rf 0.86.
Intermediate 43 5-[2-[(6-Bromohexyl]oxy]ethyll-2-thiophenemethanol A solution of Intermediate 42 (1.5g) in diethyl ether (15mA) was added dropwise to a stirred suspension of lithium aluminium hydride (0.23g) in diethyl ether (5mA) at room temperature under nitrogen. The mixture was stirrsd at room temperature for 40 minutes and then carefully quenched successively with water (0.25mi), 2N sodium hydroxide (0.25mi) and water (0.75mi). The mixture was diluted with diethyl ether (100ml), filtered through hyflo (washing with additional ethanol) and evaporated in vacuo to give an oil. Purification by FCC eluting with hexane-ether gave the title compound as a colourless oil (1.02g), t.l.c. (hexane-ether 2:1) Rf 0.16.
i At 8t t -31 Intermediate 44 N N-Diethyl--5- (2-hydroxyethy I) ]-2-thiophenesulphonamide n-Butyllithium in hexane (1.55M, 5.9mi) was added dropwise to N, N-die thyl-2-thiophen esulphonamide (2.0g) in THF (15mlZ) at -780~ under nitrogen. The solution was stirred at -780 For 30 min and ethylene oxide (1.61g) in TIIF (6mY) was added. The mixture was allowed to warm up to room temperature, stirred for 30 min, treated with saturated aqueous ammonium chloride (1O0mZ)-and extracted with diethyl ether (3x100m.Z). The dried organic extracts were evaporated in vacuo to give a brown oil. Purification by FCC eluting with ether-hexane (1:1) and ether gave the title compound as a brown oil (1.83g), 't.l.c.
(ether Rf 0.42.
Intermediate romopenty1) oxy Ie thyl]1-2-N ,N-die thylthiophenesulp honamide A mixture of Intermediate 44 1,5-dibromopentane (2.5ml), TAB and 40% sodium hydroxide solution (4mi) was stirred under nitrogen for 6h. The mixture was diluted with water (lO0mY.) and extracted with diethyl ether (2xl00mJZ), dried and evaporated in vacuo to give a brown oil. Purification by FCC eluting with hexane-ether 10:0 3:1) gave the title compound as a colourless oil (1.80g), t.l.c.
(hexane ether 3:1) Rf 0.17.
V Example 1 (2-Furanyl) ethyl] oxy] hexyl] amino] methyl]-4-hydroxy-l ,3benzenedimethanol A mixture of Intermediate 2 Intermediate 1 (1.35g), potassium iodide triethylamine (5m1) and DMF (40m1) was heated at 6OU for A3h and poured into water (500m1) The resulting emulsion was extracted with ethyl acetate (3x150m1) and the combined extracts were dried and evaporated. The sem-i-solid residue was triturated with ethyl acetate (50m1) and diethyl1 ether (30m1) to give the title compound as a white solid (0.3g) m.p. 91-930.
Found: C,66.5;H,8.1;N,3.6;
C
2 IH NOb requires: C,66.8;H,8.3;N,3.7%Q.
21 31A -32 Example 2 4-Hydroxy--a'-[ (5-p ropy I-2-f urany I) Iethy oxy I hexy I Iamino]I methyl]-1 ,3-benzenedinethanol, hemihydrate.
A mixture of Intermediate 1. (1.75g), Intermediate 4 (1g) and DMF (15m1) was heated at 750 under nitrogen for 2h. The mixture was diluted with water (150m1), extracted with ethyl acetate (3x50m1) and the extracts were washed with water (50m1) and brine (50mi) dried and evaporated in v acua to give a pale-brown oil Purification by FCC on triethy lamine deactivated silica using System B (90:10:1) as the eluant afforded an oil (0.48g) which on trituration with a cold mixture of cyclohexane and diethyl ether gave the title compound as an off-white solid (0.41g) m.p. 65-660.
Analysis Found: C,67.2;H,8.8;N,3.2.
o C 24+ 31 1 2
H
2 0 requires C,67.2;H,8.9;N,3.3%0.
Example 3 0~ a (2-Furany I) pan tyl]I oxy]I hex y IIamin oIme t hy 11-4- hy droxy-l, 3 benzenedimeth-anol A mixture of Intermediate 5 Intermediate 1 (0.87g) and DEA (C ,48g) in DMF (l0ml) was heated at 750 for 1.5h. Water (150m1) was added and the mixture acidified to pH3 with 2M hydrochloric acid, then o basified to pH8 with solid potassium bicarbonate and extracted with ethyl acetate (3x70m1). The extracts were washed with water (50m1), brine (50m1), dried and evaporated in vacua to give an oil (1.3g) which was purified by FCC (triethylamine deictivated silica) eluting with System B (85:15:1) to afford a colourless oil (0.51g).
Trituration with cold ether for 24h gave the title compound as a white powder (0.31g) m.p. 59-600.
Analysis Found: C,68.3;H,8.9;N,3.2.
C
24
H
3 /NDb requires C,68.7;H,8.9;N,3.3%0.
Example 4 4-Amino-a- [2-benzo furanyl ethoxy I pentyl amino] dichlorobenzenemetharil A mixture of Intermediate 16 Intermediate 6 (1.5g) and DEA in DMF (16m~.0 was heated at 1000 for 3h, L.c 3led and evaporated F:,3_ in vacuo. The residual oil was purified by FCC eluting with System C (94:5:1) followed by System C (90:10:1) to give a gum. Trituration with hexane (20mlZ) afforded the title compound as colourless crystals (1.22g) m.p. 49-520.
Analysis Found: C,60.1;H,6.1;N,6.0;Cl,15.6.
C H 3 2 C1 N 03.0.5H 0 requires C,60.O;H,6.35;N,6.l;Cl,l5.4%'.
Examples -5-9 were prepared accordi.ng to the method of U Example 4.
Example al-[[[6-[2-[2-Benzo(b)furanyllethoxylhexylIlaminolmethyl]-4-hydroxY- .1,3 bneeieLao From Intermediate 1 (1.20g) and Intermediate 7 (1.43g), except that System A (39:10:1) was used as eluent for the FCC purification. The title compound was obtained as a pale yellow powder (606mg) m.p.
101-1040.
Analysis Found: C,70.1; H,7.75; N,3.2.
C 2 !3H 33 NO, requires: C,70-2; H,7.8; N,3.3"0.
t t Example 6 4, 4-Amino-3,5-dichloro-a-[[[6-[3-(2-furanyl)propoxylhexyllaminolmethylI benzenemethanol From Intermediate 16 (0.8g) and Intermediate 8 except that hexane-ethanol-O.88 ammonia (44:5:1) was used as the FCC eluent, and the resulting gum was dissolved in ethyl acetate (30ml), and washed with sodium bicarbonate solution (l5ml), water (2x20m.Z), brine dried and evaporated in vacuo, before triturating the residue with hexane. The title compound was obtained a~s colourless9 crystals (192-mg) t.l.c. (System A 39:10:1) Rf Analysis Found C,58.1;H,6.9;N,6.5.
C
21
H
30 C1 2 N 2 0 3 -0.2H 2 0 requires C,58.Z5;H,7.1;N,6.5%.
Example 7 ,5-dichlorophenyl)-2-hydroxyethyllaminolhexylI oxylpropyl]-N ,N-diethyl.-2-furancarboxamide, (E)-butenedioate salt (2:1) 34 From Intermediate 16 (1.02g) and Intermediate 12 FCC purification with System C (95:3:2) and (93:5:2) eluants gave a product which was taken up in methanol (15m.) and fumaric acid (133mg) was added. The solution was evaporated in vacuo and the residue triturated with dry ether Wx) to afford the title compound as a cream powder (735mg) m.p. 100-1030.
Analysis Found: C,57-3; N,6.8; Cl,12.1.
C 26 H 39 C1 2
N
3 0 4 .0.5C 4
H
4 0 4 requires C,57.3; H,7.05; N,7.2; C1,12.4%1.
Example 8 Methyl 5-[3-[[5-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl] amino] pen tyl] oxy I propy 11-2- f urancarboxy late From Intermediate 16 (1.84g) and Intermediate 14 (1.85g), with a reaction time of lh. FCC purification eluting with System C \95:5:1) gave a colourless oil, which was triturated with ether-hexane (1:10) to give the title compound as a white solid (1.31g) m.p. 58-590.
Analysis Foundi C,55.57;H,6.39;N,5.81;Cl,l4.9.
C
22
H~
3 Cl 2
N
2 Ob requir~es C,55.82,;H,6.39;N75.92;Cl,15.0%' Example 9 E (4-Amino-3,5-dichlorophenyl)-2-hydroxyethylI amino] hexyl] oxy] butyl]-2-furanmethanol From Intermediate 16 (0.75g) and Intermediate 15 (0.75g) with a reaction time of 2.5h. FCC purification eluting with System C (95:5:1) afforded an oil which on tiituration with hexane-ether (ca 4:1) gave the title compound as a white solid (367mg) m.p. 60-610.
Analysis Found: C,58.6;H,7.3;N,6. 0;Cl,15.0.
C
23 H 314
C
2
N
2 0 4 requires C,58.35;H,7.2 5.9;Cl,15.0%0.
Example dichlorophenyl)-2-hydroxyethylI amino] pen tyl] oxy] propyl] -2-f urancarboxylic acid A solution of the product of Example 8 (0.60g) in 2N sodium hydroxide solution (5ml) and methanol (20mli) was stirred under nitrogen for 3h, then acidified to pH 6 with 2N hydrochloric acid. The solvent was evaporated in vacuo and the residue triturated with water (150mi), and then ethyl acetate (2xlO~ml). The residue was dissolved in methanol (200mlZ) and evaporated in vacuo to give a white foam (0.55 g).
Trituration with diethyl ether gave a white solid which was further triturated with hot isopropanol-methanol (ca The mixture was filtered and evaporation of the filtrate in vacuo, gave the title compound as a white solid (299mg) m.p. 89-910, t.l.c. (System A j 40:10:1) Rf 0.05.
Analysis Found: C,55.6;H,6.4;N,5.8;Cl,14.9.
C
22
H
30 C1l 2 N 2 0, requires C,55.8;H,6.4;N,5.9;Cl,15.0%' Example 11 4-Amino-3,5-dichloro-cr-[[[6-[3-[5-[ diethylamino)methyl]-2-furanylI I popoxyl hexyll amino] methyl] benzenemethanol A solution of 5-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyf rethyl] amino] hex yl11oxy Iprop yll-N,N -die th yl-2 -f urancarbox amide (0.83g) in benzene (6mtZ) was added dropwise over 10 min to a stirred suspension of lithium aluminium hydride (175mg) in dry ether under nitrogen. The mixture was stirred under nitrogen at 220 for 24h, then quenched sequentially with water (iml), 2N sodium hydroxide solution (iml) and water (2ml). The Mixture was filtered through hyflo and the solids washed with toluene-ether 10mY.). The combined filtrate and washings were dried and evaporated in vacuo to an oil. Purification by FCC eluting with System C (93:5:2) afforded the title compound as a pale yellow oil (0.59g), t.l.c. (System A 39:10:1) Rf Analysis Found :C,60.9; H,8.2; N, 2.
C
26 H 4 1 C1 2
N
3 0 3 requires C,60.7; H,8.0; N,8.2%.
Example 12 [6-4 (2-Furanyl)hexylloxylhexyllamino-l-hydroxyethyl-2hydroxyphe ny 11met hanesu lphonamide, benzoate salt (1:1) A solution of (2-amino-l-hydroxyethyl)--2-hydroxyphenyllmethanesulphone~mide (0.95g), (6-bromohexyl)oxylhexyllfuran (0-84g) and DEA (0.54mZ) in DMF (2Omi) was heated at 90D for 5h, then evaporated in vacuo. The residue was purified by FCC with System A (39:10:1) eluant, to afford a product which was dissolved in methanol (6mlz) and a-- -36 treated with benzoic acid (21mg). The solvent was evaporated in vacuo and the residue triturated with dry ether to give the title compound as a beige solid (75mg), t.l.c. (System A 39:10:1) Rf 0.15.
Analysis Found: C,60.3; H,7.3; N,4.6.
C
32 H 46N 20 8-H 2 euires C,60.4; N,4.4%0.
Example 13 Methyl 5-[6-[[6-[[2-hydroxy-2-[4-hydroxy-3 E[(methanesulphonyl) amino]pheyllJthllamino] hexyl] oxy] hex 11-2- f urancarboxy late,_ benzoate salt A soluti Ion of [5-[2-amino-1-hydroxyethylj-2-hydroxyphenylI methanesuiphonamide (0.95g), methyl 5-[6-[(6-bromohexyl)oxylhexyl] -2-furancarboxylate (1.00g) and DEA (0.37g) in DMF (20ml) was stirred at ca, 1000 for 3h. The solvent was evaporeted in vacuo and the residue dissolved in methanol (15m.Z) and absorbed onto silica (Merck 9385, l5ml). Purification by FCC elutitig with System A (40:10:1) gave a brown oil which was purified by FCC as above. The resulting brown oil in methanol (l5m.) was treated with benzoic acid (0.04g), evaporated in vacuo and triturated with diethyl ether to give the title compcund as a cream solid (0.203g), m.p. 96-980.
Analysis Found: C,57-7; H,6.9; N,4.2.
C.H
42 N 0 S.C/H 0.1.5H 0 requires C,58.0; H,7.3; Example 14 N ,N-Diethyl-5-[6-[ E6-[ [2-hydroxy-2-[4-hydroxy-3-[ (methanesulphonyl) amino] phenyll ethyl] amino] hexyll oxyj hexyl]-2-f urancrboxamide A solution of N- [5-[[2-amino-1-hydroxy]I ethyl] (hydroxy) phenyl]Imethanesuiphonamide (0-98g), ,-diethyl (6-bromohexyl)oxy]hexylll-2-furancarboxamide (0.69g) and DEA (0.25g) was treated according to the method of Example 13 except the reaction time was 2 hours and treatment with benzoic acid was omitted. The title compound was obtained as a brown oil (0.141g), t-l-c. (System A 40:10:1) Rf 0.1.
Analysis Found: C,58-6; H,7.9; N,6.9.
C 3 0 H 4N 3 0S.H H 2 0 requires C,58.7; H,8.4, N,6.9,1.
-37- Example N-[5-[2-[[6-[[6-(2-Furanyl)hexylloxylhexyllamino] d-hydroxyrthyl>hydroxyphenyl] methanesuiphonamide, I-hydroxy-2-.napthoaty, salt A solution of [6-[[6-(2-furanyl) hexylloxylthexyllamino]-lhydroxye th yl -2-hydroxyp hen y ]me thanes u.phon afri', benzoate salt (426mg) in methanol (4mY) was partitioned betweer. 8% sodium bicarbonate (15m.Z) and ethyl acetata (4OmXZ) and the aqueous phase further extracted with ethyl scetate (20mlZ). The combined organic extracts were dried and evaporated in vacuo to a gum which was taken up in methanol (5mX). 1-Hydroxy-2-naphthoic acid (129.5mg) was added, the solution evaporated in vacuo and the residue triturated with dry ether (x2) to give the title compound as an off-white solid (420mg) M.P. 108-l090.
Analysis found: C161.75; H1,7.0;
C
2 5H 4 oN 2
O
6
S.CIIH
8 o 3
.H
2 0 requires C,61.5; N,4.0%1.
Example 16 N- b] furany.0butoxy Ihexyll amino I-1-hydroxyethy I- 2-hydroxyphenyllmethanesulphonamide benzoate (salt) A solution of 2-[4-[(6-bromohexyl)oxylbutylllbenzo[blfuran (790mg) [2-aaaino-1-hydroxyethyl]-2--hydroxyphen yllmethanes ulphonamide (1 .07g) and DEA (Il.2g) in 014F (20m.Z) was stirred at 100 0 f or 3h. The solvent was evaporated in vacuo to leave a pale brown residue (2.2g) which was purified by FCC eluting With System A (90:10:1+*80:20:1) to give the base as a pale yellow oil (45mg). A solution of this in methanol (10m.0) was treated with benzoic acid (11mg), the solvent evaporated and the residue triturated under ether (l1mY.) to give the title compound as a light brown solid (55mg), m.p. 79-800.
Analysis Found:C,62.3; H1,7.1; N,4.5;
C
2 1
H
38
N
2 0 6
S.C/H
6 0 2 .0.85 H 2 0 requires C,62.2; H1,7.0; N,4.3; S,4.9%' Example 17 2[ (2-benzo[ bIf uranyl) butoxy Ihexyll amino] -1-hydroxyethyl I- 2-hydroxyphenyllmethanesulphonamide 4,4'-methylenebis[3-hydroxy-2naphthalene carboxylatelsalt A solution of 2- (6-bromohexyl)oxy ]but yl lbenzo[ b~furan N- (2-amino-l-hydroxye thyl 1)-2-hyd roxyp henylI Ime than esulphonamide y 38 (1.48g) and DEA (J..0m2) in DMF (25mr.Z) was heated at 8001 under ;-iitrogen, for 4h, and the solvent was eva-porated in vacuc to leave a dark brown oil. Purification by FCC eluting -ith System A (90:10:1) yave the free base as an immobile yellow oil (1.2 A portion of the base (341mg) in methanol (20m1) was heated under reflux ,iith pamoic acid (170mg) in methanol (5m1) for 0.5h. The clear solution was evaproated to give the title compound as a yellow foam (521mo,), m.p.
99 -100.
Analys4s Found:C,d3.9; H,6.5; N,3.7; S,4.25.
C71H 3 8 N 2 0 6 S1/ 2
C
2 3
H
1 6 0 6 -0.5H 2 0 requires C,64-1; H,6.6; N,3.9; 4-H ydroxy- 1 (2-thienyl) but oxy] hexyl]I amino] methyl] -l ,3-benzenedimethanol k~ -i,xture of Intermediate 26 DEA (0.45g), Intermediate 1 (0.85g) and DM.F (l0ml) was heated at 750 for 2h. The mixture was diluted with water, acidified to pH 3 with 2M HCl, basified to pHB with solid sodium bicarbonate and extracted with ethyl acetate (2 x 80m1). The ,~tracts wrjre washed wi-"h water (50ml) and brine (50m1) dried and evaporated in vacuo to give an oil (1.3g) which was purified by FCC on triethylamine deactivated silica using System B (85:15:1) as the eluant to give the product as an oil (0-46g). Trituration with cold aiethyl ether gave the title compound as a whit2 solid (0.33g) m.p.
64-650.
Analysis Found: C,65.8;H,8.3;N,3.3
C
23 H NO S re~jires: C,65.5;H,8.4;N,3.4%.
Example D~ 4-Hydroxy-a 1 -[E[6-[3.-(5-.mathyl-2-thienyl)propoxylhexylI amino mebl 1-113- beni.enedimethanol
A
1 solution of IntermPediate 28 (1.00g), DEA (0.81m1), Intermediate I (0.86g) and DMF (l0ml) was heated at 75-800 for 2.5h. The mixture wa diluted wir^ water (100ml), acidif4-d to pH 3 with 2M hydrochloric acid, basified to pH8 with solid potassium hydrogen carbonet--- end extracted with ethyl acetate (3x5Om1). The combined extracts were at room temperature for 18h, diluted with water (50ml), and extracted 1 I I I I ~C l~ r a 1 aa 39 washed with water (50ml) and brine (50ml), dried and evaporated in vacuo to give an oil which was purified by FCC on triethylamine deactivated silica using System B (80:10:1) as the eluent to give the product as a viscous oil. Trituration '.th cold ether gave the title compound as a white solid (460mg) m.p. 59-62 T.l.c. (Et 3
N
deactivated Si02, ethyl acetate-methanol 8:1) Rf 0.24.
Example ,1-Dimethyl-6-[2-(2-thienyl)ethoxy] hexyl amino] methyl]-4-hydroxy-1,3- benzenedimethanol,benzoate (salt) A solution of methyl-5-(bromoacetyl)-2-hydroxybenzoate (1.93g), Intermediate 31 and DEA (0.9g) in ethyl acetate (30ml) was refluxed for 4h and evaporated. The residue was extracted with diethyl ether (50ml) and the solution fdded drcpwise to a suspension j of lithium aluminium hydride l1.0g) in diethyl ether (50ml) at 00.
SThe mixture was stirred at room temperature for 3h, treated cautiously I with water (10ml), acidified to pHl with hydrochloric acid and basified to pH 8 with solid potassium carbonate. The resulting slurry was extracted with ethyl acetate (3x200ml) and the dried extract was evaporated. The residue was purified by FCC eluting with System B (90:10:1) to give a yellow oil The oil in chloroform was added to benzoic acid (0.2g) in chloroform (5nl) and the chloroform was removed by evaporation. The resioue was triturated i with diethyl ether (10ml) to give the title compound as a cream solid S(0.05g) m.p. 85-900. T.l.c. (System D 9:1:0.1) Rf 0.2.
ii xample 21 4-Hydroxy-a~-[ [[l-methyl-6-[ 2-(2-thienyl) ethoxy]hexyl] 1 amino]methyl]-1,3- benzenedimethanol.
i A solution of Intermediate 1 (0.84g), Intermediate 32 (l.lg) and acetic acid (0.276g) in methanol (20ml) was treated with sodium cyanoborohydride (0.2g) and stirred for 18h under nitrogen.
Saturated aqueous sodium bicarbonate (50ml), was added and the mixture was extracted with ethyl acetate (3x50ml). The dried extract was evaporat d and the residue was purified by FCC eluting with System B e-
A
I
I
I
#4 4 4* 14 I I 4 l~ 4~4II 4 44 4 I 4 4'4 1? I S It 40 to give the title compound as a white solid (0.8g) m.p.
68-700.
Analysis Found: C,64.8;H,8.2;N,3.3.
C
22
H
33 NO 4 S requires C,64.8;H,8.2;N,3.4%0.
Example 22 2- (Benzo[ b] thienyl) ethoxyl hexyl] amino] methyl]-4 -hydroxy-l,3- benzenedimethanol litermediate 33 (1.55g), intermediate 1 (1.00g), DEA (1.29ml) and DMF (l4ml) wert stirred at 95- 1000 under nitrogen for lb. The cooled mixture was evaporated (1 Torr), treated with aqueous saturated sodium bicarbonatq (50m1), and extracted with ethyl acetate (3x50m1). The combined, dried organic extracts were evaporate d onto silica gel (Merck 7734, 5g), and the resultant silica gel plug applied to an FCC column. Elution with System B (94:5:1+~89:10:1) afforded, after triturat-.on with ether, the title compound as a white snlid (414mg), m.p. 111-114.50. T.l.c. (NEt 3 deactivated Si0 2 System B 89:10:1) Rf 0.06.
Example 23 .Propyl 5-[3-[[6-[[2-hydroxy-2-[4-hydroxy-3- (hydr xymethyl) p heny I ethyl] amino] hexyll oxy] p ropy 1]-2thi op henacerboxy late hydrobromide A solution of Intermediate 36 (1.96g) in dry DNF (3m.Z) was added to a solution of Intermediate 1 (1.83g) and DEA (2-6g) in dry DMF (30m.Z) at 1000. The solution was stirred for 3h, the solvent was evaporated and the residue was purified by FCI eluting with System A (80:20:1) to give a brown oil (1.75g). Trituration of this oil with diethyl ether gave the title compound as a cream solid (540mg) m.p. 69-710.
Analysis Found: C,54.60; H,7.30; N,2.43; 5,5.78.
1 26
H
39
NO
6 S.HBr requires C,54.35; H,7.02; N)2.44; S,5.58,19.
Example 24 4-Hydroxy-.a 1 (,-thienyl)propoxylhexyl] amino] -41met hyl]-1, ,3-be nzenedime then ol Intermediate 37 (1.53g) was added to a stirred solution of Intermediate 1 (1.83g) and DEA (2.6g) in DMF (30m2Z) at 8&P and the solution was stirred for 2h. The DMF was evaporated and the residual oil was purified by FCC eluting with System A (80:20:1) to give an imber oil (1.4g) which was triturated with ether to give the title compound as a white powder (900mg) m.p. 86-880. T.l.c. (System A 80:20:1) Rf 0.24.
Example [1-Hydroxy-2-[ (2-thienyl) butoxyl hexyll amino] ethyl]-l,3-benzenediol, (E)-2-butenedioate (salt) A qolution of Intermediate 26 (800mg) in dry DMF (lmY) was added to a stirred solution of 5- (2-amino-l-hydroxyethyl)-l, 3-ben zenediol (700mg) and DEA (1-29g) in dry DMF (l5mZ) at 1000 and stirred at 1000 for 2h.
The solvent was evaporated and the residue was pj ~ified by FCC elutin~g with System A (80:20:1) to give a straw coloured oil (550mg). The oil in methanol (5mZ) was added to a solution of ftxnaric acid (100mg) in methanol the methanol was evaporated and th. residual oil was triturated with dry ether to give the title compound as an off-white powder (550mg) 123-1240. T.l.c. (System A 80:20:1) Rf 0.25.
Example 26 (5-Chioro-2-thienyl) propoxyl hexyl I amino] 1-hydroxyethyl]-2-hydroxyphenyl] methanesulphonamide A solution of Intermediate 38 (1.02g) in ONE (2m.Z) was added to a stirred solution of N- (2-amino-1-hydrox-yethyl )-2-hydroxyphenyl]methanesulphonamide (1.5g) and DEA (1.55g) in dry DMF (20m.Z) at 1000~ 4 and the resulting red soluti-on was at'~ t 1000 for 2h. The solvent was evaporated and the resid. ea purified by FCC eluting with System A (80:20:1) followed by tUituration with dry ether to give the title compound as a fawn powder (390mg) m.p. 85-870. T.l.c.
(System A 80:20:1) Rf 0.19.
A
LI
I
1
I
44 0 4 4 44 .4 4 4 4 4 4, #4 4, 4 4* 4 o o 04 4.0 04 4 .0 44 4 04 t 4 44 .04 4 14~ 42 Example 27 5- (4-Amino--3 ,5-dichloropheny l)-2-hydroxyethyl Iamino Ihexyl] oxylethylII-N,N-diethyl-2--thiophenecarboxamide, (E)-butenedioate salt (2:1) A solution of Intermediate 16 (0.47g), (6-bromohexyl)oxylethyl]-2-N,N-diethylthiophenecarboxamide (0.55g) end DEA (0.22g) in DMF (10m.0 was treated according to the method of Example 25 except the FCC eluant used was System C (98:2:1+95:5:1). The title compounO was obtained as a white solid Analysis Found: C,54.9; H,6.7; N,7.0; C1,11.9.
C
25
H
3 /C1 2
N
3 0 3 S.0.5C 4
H
4 0 4 requires C,55-1; H,6.7; N,7.1; C1,12.0%.
Example 28 [2-(4-Amino-3 ,5-dichlorophenyl)-2-hydro yethyll amino] hexyll oxylethyll-.2-thiophenemethanol, (E)-butenedioate salt (2:1) A solution of Intermediate 16 (0.98g), (6-bromohexyl)oxylethyl-2-thiophenemethanol (0.95g) and DEA (0.46g) in DMF (18m.0) was treated according to the method of Example 25 except that the FCC eluant was System C (98:2:1-*95:5:1).
The title compound was obtained as a cream solid (0-635g), m.p.
108-1O90.
Analysis Found: C,52.3;H,6.l;N,5.l;Cl,13.61
C
2 1
H
30 C1 2
N
2 0 3 S.0.5 C 1 4H 4 0 4 .0.5 H 2 0 requires C,52.3;H,6.3;N,5.3;Cl,13.4%' Example 29 Methyl 5-[2-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyllamino] hexyll oxy] e thy thiop heneca rboxy late A solution of Intermediate 16 (1.19g), methyl (6-bromohexyl)oxylethyll-2-thiophenecarboxylate (1.25g) and DEA (0.56g) in DMF (20mk) was stirred at ca 1000 for 2.5h. The solvent was evaporated in vacuo and the residue purified by FCC eluting with System C (98:2:14*95:5:1) to give a yellow oil.
Trituration with hexane-ether gave the title compound as an off-white solid (0.839g), m.p. 77.5-78.50.
"Owl -43 Analysis Found: C,53.85; H,6.09; N,5.62; Cl,14.75.
C
22 H 3 0C1 2 N 2 0kS requires C,523.99; H1,6.18; N,5.72; C1,14.49%1.
Example 4-Amino-3, 5-dichlorophenyl)-2-hydroxyethylI amino] hexyl]oxylethl]--thopheecaboxlicacid A solution of methyl (4-'aminc--3, 5-dichlorophenyl)-2hydroxyethyll aminolhexyljoxy ]ethyl] -2-thiophenecarboxylate (0.274g) in a 2N sodium hydroxide solution (4.5miZ) and methanol (20m.Z) was stirred at room temperature under nitrogen for 28h. Dowex 50 (H1+) methanol-washed ion e~change resin was added portionwise to neutralise the mixture to p117. The mixture was filtered and evaporatf;d in vacuc to give an orange solid. Trituration with hexane gave the title compound as a yellow solid (229mg), m~p. 178-1850 (decomp).
Analysis Found: C,52.0; H,6.0; N,5.6; C1,14.2.
C
2 1
H
2 8 C1N 0 S.0.5H 0 requires C,52.1; H,6.0; N,5.8; C1,14.6'%.
Example 31 N ,N-Diethyl-5-[2-[ (4-amino-3 ,5-dichlorophenyl)-2-hydroxyethylilaminolpentylloxylethyl]-2-thiophenesulphonamide (E)-hutenedioate salt (2:1) A solution of Intermediate 16 (0.48g), (5 -bromopentyl) oxy leth yl]-2-N, N-dieth ylt hiop her sulphonamide (0.6g) and DEA (0.23g) in DMF (l0mi) was stirred at c 1000 for under nitrogen. The solvent was evaporated in vacuo t -,give a brown oil. Purification by FCC elutiqg with System C (95:5:1) gave a yellow oil which was dissolved in methanol (30m.0) and treatied with fumaric acid (0.043g), evaporated in vacuc and triturated with ether to give the title compound as a cream solid (0.531g), m.p. 127-1290.
Analysis Found: C,49.0;H,6.3;N,6.5;Cl,ll.6.
C 23 H 3Cl 2 Nd 0 4 5 2' 0 5 C 4H 40 4 requires C,49.2;H,6.1;N,6.9;C,L1.6%4 Example 32 [[6-[2-(2-Benzo[blthienyl)ethoxylhexyllaminolmethyl]-4-hydroxy-1 ,3 benzenedimethanol, 4, methy lenebis hy droxy-2- naphthalene carboxylate)salt (2:1) -44 A solution of a l -[[[6-[2-(2-benzo[b]thienyl)ethoxy]hexyl]amino]methyl] -4-hydroxy-1,3-benzenedimethanol (0.378g) in methanol (20mA) was treated with 4,4'-methylenebis (3-hydroxy-2-naphthalene carboxylic acid) (165mg) and heated at reflux for lh. The mixture was cooled to room temperature, filtered and evaporat-d in vacuo. Trituration with dry ether afforded the title compound as a yellow foam (380mg) m.p.
86-93 0 Analysis Found: C,67.9; H,6.8; N,2.15; S,4.9.
d C 2 5
H
3 8 N0 4 S.0.5.C 2 3
H
1 6 0 6 .0.4H 2 0 requires C,68.0; H,6.5; N,2,2; The following are examples of suitable formulations of compounds of the invention. The term 'active ingredient' is used herein to L represent a compound of the invention.
I .Tablets (Direct Compression) mg/tablet Active ingredient Microcrystalline cellulose USP 196.5 Magnesium Stearate BP Compression weight 200.0 The active ingredient is sieved through a suitable sieve, blended with the excipients and compressed using 7mm diameter punches.
Tablets of other strengths may be prepared by altering the ratio of active ingredient to microcrystalline cellulose or the compression weight and using punches to suit.
The tablets may be film coated with suitable film forming materials, such as hydroxypropylmethylcellulose, using standard techniques. Alternatively, the tablets may be sugar coated.
'PIU Y"I~ 45 Metered Dose Pressurised Aerosol (Suspension Aerosol) mg/metered dose Per can Active ingredient micronised 0.100 26.40mg Oleic Acid BP 0.010 2.64mg Trichlorofluoromethane BP 23.64 5.67g Dichlorodifluoromethane BP 61.25 14.70g The active ingredient is micronised in a fluid energy mill to a fine particle size range. The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15 0 C and the micronised drug is mixed into the solution with a high shear mixer. The suspension is metered into aluminium aerosol cans and suitable metering valves delivering 85mg of suspension are crimped onto the cans and the dichlorodifluoromethane is pressure filled into the cans through the valves.
SInhalation Cartridges mg/cartridge Active ingredient micronised 0.200 Lactose BP to 25.0 The active ingredient is micronised in a fluid energy mill to a fine particle size range prior to blending with normal tabletting grade lactose in a high energy mixer. The powder blend is filled into No. 3 hard gelatin capsules on a suitable encapsulating machine. The contents in the cartridges are administered using a powder inhaler such as the Glaxo Rotahaler.
A
Claims (8)
1. A compound of formula (I) R 18 RI I I Ar-CHCHNHCXCH 2 OCH 2 yQ(I OH R or a physiologically acceptable salt or solvate thereof, wherein HOR 3 15 Ar :.epresents HO where R 3 is a straight or branched 3 alkylene group, 20 R (b) R where one of R 4 and R5 is a hydroxy group and the other is a hydrogen or halogen atom or a hydroxy group, R 6 NH(CH 2 )p HO where R 6 is a group R 7 CO-, PJNHCO-, R 7 R 8 NS0 2 Or R 9 S0 2 (where R 7 and R 8 each represent a hydrogen atom or a C 1 jalkyl group and R 9 is a C 1 3 alky1 group) and p is an 5973/1 47 integer 0 or 1, R 1 6 R 17 HO wher R 16 and R 1 each represent a hydrogen atom or a Cl.. 4 alkyl group, or, when R 1 6 is a hydrogen atom, R 1 7 may also represent a C 1 4 alkoxycarbonyl group, R 10 OCHi 2 HO-i' where R 10 is a Cl 1 3 alkyl group, Cl F 3 C 2 (Mf Y! 2 N H 2 N- Cl HO CH 3 SO 2 CH 2 HO HOCH 2 NCCH 2 HO-i or 59 73/1 48 I or N N O H 0 0 OH OH H X represents a bond or a Cl- 7 alkylene, C 2 7 alkenylene or C2- 7 alkynylene chain, Y represents a bond or a C 1 6 alkylene, C2-6alkenylene or C2-6alkynylene chain, with the proviso that the sum total of carbon atoms in X and Y is 2 to R 1 and R 2 each represents a hydrogen atom or a Cl- 3 alkyl group with the proviso that the sum total of carbon atoms in R 1 and R 2 is not more than 4; f415 R 18 represents hydrogen or Cl_3alkyl; R 1 1 R 1 1 Q represents a R 12 P 12 I tr or group; where S o z Z represents an oxygen or a sulphur atom; R 11 represents a hydrogen or halogen atom or a group Cl-3alkyl, nitro, -(CH 2 )tR, -(CH2)rCOR 13 or S0 2 NR 14 R 1 5 R 1 2 represents a hydrogen atom or a C 1 -3alkyl group, or, when R 11 represents a halogen atom, R 12 additionally represents a halogen atom; R represents a hydroxy, C1-3alkoxy or NR 1 4 R 15 group; R 13 represents a hydroxy, C 1 -4alkoxy or NR 14 R 15 group; R 14 and R 15 each represents a hydrogen atom or a C1- 4 alkyl group or NR 1 4 R 15 forms a saturated heterocyclic amino group 5973/1 I. I. li L-~ 4 A 49 which has 5-7 ring members and optionally contains in the ring one or more atoms selected from or or a group -NH- or -N(CH 3 t represents an integer from 1 to 3; r represents an integer from 0 to 3.
2. A compound according to Claim 1 wherein Z is oxygen. .0 3. A compound according to Claim 1 wherein Z is 1 sulphur.
4. A compound according to any one wherein Ar is selected from of Claims 1 to 3 H 2 N CH 3C O 2 NH HO- and HO A compound according to any wherein X and Y are both alkylene.
6. A compound according to any wherein R 1 and R 2 are both hydrogen.
7. A compound according to any wherein R 18 is hydrogen. one of Claims 1 to one of Claims 1 to one of Claims 1 to 5973/1
8. A compound according to any one of Claims 1 to 7 wherein Q is iior
9. A compound selected from:- czl- C C6- C 5- (2-furanyl) pentyl] oxy] hexylaminomethyl]-4- hydroxy-l, 3-benzenedimethanol; [2 -E6-L6- (2 -f uranyl) hexyl. ]oxy~hexyl] amino] -1- hydroxyethyl) -2-hydroxyphenyl] methanesuiphonamide- [6-E C 2-(4-amino-3, 5-dichlorophenyl) -2-hydroxyethyl) amiino~hexyl]oxy]propyl]-NN-diethyl-2-furancarboxamide; IS 4-hydroxy-cx 1
16-C3- (3-thien ,1)propoxy~hexyl~amino]methyl] 3-b~enzenedimethanol; cx 1 -[[E6-(2-(benzo(b~thienyl)ethoxy~hexyl]amnino]methyl]-4- hydroxy-l, 3-benzenedimethanol; V. 5-fl-hydroxy-2-(E6-EE4-(2-thienyl)butoxyjhexyl]aminojethyl] 3-benzenediol; cx -C(6-(2-C2-benzo~b]furanyl~ethoxy~hexyl~amino~methy]-4- hydroxy-1, 3-benzenedimethanol; N-E5-[2-CE6-(4-(2-benzo(b~furanyl)butoxy~hexyl)amino)-l- hydroxyethyl] -2-hydroxyphenyl~methanesulphonamide; 26 4-hydroxy-cx'-E(E6-(4-(2-thienyl)butoxy~hexyl~amino~raethyl] 3-benzenedimethanol; a 1- C[1,l1-dimethyl-6- C2- (2-thienyl) ethoxyihexyl ]amino) methyl] -4-hydroxy-l, 3-benzenedimethanol; 6-E E2-(4-amino-3,5-dichlorophenyl)-2-hydroxylethyl3 TO0 amino~hexyljoxyj ethyl] -l,N[-diethyl-2-thiophenecarboxamide; and their physiologically acceptable salts and solvates. A pharmaceutical formulation comprising a compound of formula as defined in any one of Claims 1 to 9 together with a physiologically acceptable carrier or excipient. 1 -51- 11. A method of treating a patient suffering from a disease associated with reversible airways obstruction which comprises administering to said patient an effective amount to alleviate said disease of a compound of formula aF, defined in claim 1 or a physiologically acceptable salt or solvate thereof. 12. The method according to claim 11 wherein said disease is asthma or chronic bronchitis. 13. A method of treating a patient suffering from a condition selected from premature labour, depression, congestive heart failure, an inflammatory or allergic skin disease, glaucoma or a condition in which there is an advantage in lowering gastric acidity which comprises Sadministering to said patient an effective amount to alleviate said condition of a compound of formula as defined in claim 1 or a physiologcally acceptable salt or solvate thereof. 14. The method according to claim 13 nerein the condition requiring a lowering in gastric acidity is gastric or peptic ulceration. A compound according to claim 1, a method for the preparation thereof, a pharmaceutic'] composition comprising a said compound or a method of treatment according to claim 11 or 13 substantially as hereinbefore S' described with reference to the Examples. DATED this 27th day of May, 1991 GLAXO GROUP LIMITED BY DAVIES COLLISON Patent Attorneys Ior the applicant(s) 0 910527,ejhspe.020,26932.spe,51 L
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8729597 | 1987-12-18 | ||
| GB878729596A GB8729596D0 (en) | 1987-12-18 | 1987-12-18 | Chemical compounds |
| GB8729596 | 1987-12-18 | ||
| GB878729597A GB8729597D0 (en) | 1987-12-18 | 1987-12-18 | Chemical compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2693288A AU2693288A (en) | 1989-06-22 |
| AU613687B2 true AU613687B2 (en) | 1991-08-08 |
Family
ID=26293218
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU26932/88A Ceased AU613687B2 (en) | 1987-12-18 | 1988-12-16 | Ethanolamine derivatives |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU613687B2 (en) |
| IE (1) | IE883767L (en) |
| TW (1) | TW199150B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1203810A (en) * | 1966-12-30 | 1970-09-03 | Degussa | A process for the preparation of novel heterocyclic aminoalcohols |
| EP0178919A2 (en) * | 1984-10-17 | 1986-04-23 | Glaxo Group Limited | Aminophenol derivatives |
| AU5861586A (en) * | 1985-05-14 | 1986-12-04 | William John Louis | 3-aminopropyloxyphenyl derivatives their preparation and pharmaceutical compositions containing them |
-
1988
- 1988-12-16 AU AU26932/88A patent/AU613687B2/en not_active Ceased
- 1988-12-16 IE IE883767A patent/IE883767L/en unknown
-
1989
- 1989-06-15 TW TW078104607A patent/TW199150B/zh active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1203810A (en) * | 1966-12-30 | 1970-09-03 | Degussa | A process for the preparation of novel heterocyclic aminoalcohols |
| EP0178919A2 (en) * | 1984-10-17 | 1986-04-23 | Glaxo Group Limited | Aminophenol derivatives |
| AU5861586A (en) * | 1985-05-14 | 1986-12-04 | William John Louis | 3-aminopropyloxyphenyl derivatives their preparation and pharmaceutical compositions containing them |
Also Published As
| Publication number | Publication date |
|---|---|
| TW199150B (en) | 1993-02-01 |
| AU2693288A (en) | 1989-06-22 |
| IE883767L (en) | 1989-06-18 |
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