AU690258B2 - Substituted pyridine leukotriene B4 antagonists - Google Patents

Substituted pyridine leukotriene B4 antagonists Download PDF

Info

Publication number
AU690258B2
AU690258B2 AU22569/95A AU2256995A AU690258B2 AU 690258 B2 AU690258 B2 AU 690258B2 AU 22569/95 A AU22569/95 A AU 22569/95A AU 2256995 A AU2256995 A AU 2256995A AU 690258 B2 AU690258 B2 AU 690258B2
Authority
AU
Australia
Prior art keywords
oxy
compound
formula
pyridinyl
diphenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
AU22569/95A
Other versions
AU2256995A (en
Inventor
Noal Cohen
Ferdinand Kwo-Chen Lee
Keith Alan Yagaloff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Publication of AU2256995A publication Critical patent/AU2256995A/en
Application granted granted Critical
Publication of AU690258B2 publication Critical patent/AU690258B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Description

I 'WI'I)O(S'AI'SpI/C'I~6IO87O.pl -23/1198 Substituted pyridine I eukotriene b4 antagonists The invention relates to compounds of the formula R 3 (Xht(CR 5 R 6 )'y R1 N G{CH2)rr(O)z\z whierein X isO0 or C=O0; Y is CN, S(O),,R 8
NR
5
SO,
2
R
8
OR
9 RIO or -CAEIR."; Z is -(O)y-(CR 5
R
6
X,-R'
0 -(O)y-(CRsR 6
X,-OR
9 or RO R' are, independently, aryl, substituted aryl, hieteroaryl, lower alkyl or optionally substituted aralkyl; R' is hydrogen, lower alkyl, halogen'or lower alkoxy; is hiydrogen or lower alkyl; R' are, independently, each occurrence, hydrogen or lower alkyl; RW is hiydroxy, lower alkoxy or NR 5
R
6 R' is lower alkyl, aryl, substituted aryl or optionally substituted aralkyl; is hiydrogen, lower alkyl, aryl, substituted aryl, optionally substituted aralkyl, lower alkanoyl or aroyl; is COR', CONHSO 2 R.1 or in is an integer from 3 to 8; n and s are, independently, an integer from I to 12; o: t is an integer from 0 to 1; u is an integer from 0 to 2; v is an integer from 2 to 12; I WO 95/28386 PCTYEP95/01262 -2y is an integer and z is an integer 0 and z is an integer 0 with the proviso that either Y is R 1 0 or -C6H4R 1 0 or Z is
(CR
5
R
6 )s-R10 or R 1 0 and the further proviso that when n=l, Y is R 10 or -C6H4R 1 0 an optical isomer when R 5 and R 6 are not both hydrogen or the same lower alkyl and, when R 7 is hydroxy, a pharmaceutically acceptable salt thereof with a base.
The compounds of formula I are potent leukotriene B4 antagonists and are therefore useful in the treatment of inflammatory diseases such as psoriasis, rhinitis, chronic obstructive pulmonary disease, inflammatory bowel disease, asthma, acute respiratory distress syndrome, cystic fibrosis, allergy, arthritis such as rheumatoid arthritis, dermatitis such as contact dermatitis, NSAID-induced gastropathy, gout, ischemia/ reperfusion injury, and trauma-induced inflammation, such as, spinal cord injury.
In another aspect, the invention relates to pharmaceutical compositions and methods of use comprising the compound of formula I.
25 As used herein, the term "aryl" preferably denotes naphthalenyl, phenyl, anthracenyl, phenanthrenyl or the like.
The term "substituted aryl" preferably denotes an aryl group which may be mono-, di- or trisubstituted by, for example, halogen, trifluoromethyl, lower alkyl, phenyl, lower alkoxy, cyano or nitro or combinations thereof.
The term "heteroaryl" denotes a 5- or 6- membered aromatic heterocyclic radical containing one or more hetero atoms, selected from nitrogen, oxygen and sulfur, which radical may optionally be substituted by one or two lower alkyl, lower I I I "slqglER lldP~ 1~3~sB~ WO 95/28386 PCT/EP95/01262 -3alkoxy groups, chlorines or fluorines. It is understood that heterocyclic refers to a carbocyclic moiety in which one or more of the carbons are replaced, independently, by oxygen, nitrogen or sulfur.
Exemplary of 5- or 6- membered aromatic heterocyclic radicals are pyridinyl, imidazolinyl, thienyl, 2-chlorothienyl, furyl, pyrimidinyl, oxazolinyl or the like.
The term "lower alkyl", denotes a straight or branched chain saturated hydrocarbon containing 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, heptyl, and the like.
The term "aralkyl" denotes an alkyl group substituted by an aryl group, for example, benzyl, phenethyl, or the like, which may be substituted by halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, nitro or the like.
The term "halogen" denotes all the halogens, bromine, chlorine, fluorine, and iodine.
The term "lower alkoxy" denotes an alkyl ether group in which the alkyl group is as described above, for example, methoxy, ethoxy, propoxy, pentoxy and the like.
The term "lower alkanoyl" denotes a primary or secondary alkanoyl group containing up to 7 carbon atoms such as acetyl, propionyl, butyryl, isobutyryl and the like.
The term "aroyl" preferably denotes the benzoyl group or a substituted benzoyl group, for example a nitrobenzoyl group such as p-nitrobenzoyl or a halobenzoyl group such as m- or p-iodobenzoyl.
~B~Z P~ ma~ ra~lillapnnrrsl~-sa~~- PCT/EP95/01262 WO 95/28386 -4- The group -C6H4R10 may be ortho, meta or para substituted.
Exemplary of the group -(CR 5
R
6 are 1,1-dimethylpropylenyl, 2,2-dimethylpropylenyl, 2,6-dimethylheptylenyl, 1methyl-l-ethylpentylenyl, 1-ethyl-3-methylhexylenyl or the like.
As used herein, a leaving group denotes halogen, preferably, bromine and iodine; lower alkylsulfonyloxy, such as, (methylsulfonyl)oxy, (trifluoromethylsulfonyl)oxy or the like; arylsulfonyloxy, such as, para-toluenesulfonyloxy or the like.
As used herein, an acid sensitive hydroxyl protecting group denotes any protecting group for hydroxyl which can be cleaved by acid treatment, such as tetrahydropyranyl, trityl, 1ethoxyethyl and the like, A preferred group of compounds of formula I is one in which R1 and R 3 are aryl and R 2 and R 4 are hydrogen.
A further preferred group of compounds of formula I is one in which R 1 and R 3 are aryl, R 2 and R 4 are hydrogen, Y is S(O)uR 8
OR
9 or R 10 and Z is -(0)y(CR 5
R
6 )s-RO1 or
(CR
5
R
6 )v-OR9.
A more preferred group of compounds of formula I is one in which R 1 and R 3 are aryl, R 2 and R 4 are hydrogen, Y is R 10
Z
is -(O)y-(CR5R 6 )v-OR 9 or -(0)y-(CR 5
R
6 )s-R 10 or R 7 is hydroxy,
R
9 is hydrogen, and R 10 is -COR 7 A most preferred group of compounds of formula I is one in which R 1 and R 3 are aryl, R 2 and R 4 are hydrogen, X is O, z is zero, t is 1, n is 3-5, Y is R 10 Z is -(O)y-(CR 5
R
6 )v-OR 9 or i I- I Isns~-- r WO 95/28386 PCT/EP95/01262
(CR
5
R
6 y is zero, s or v is 2-6, R 7 is hydroxy, R 9 is hydrogen, and RIO is -COR 7 Another more preferred group of compounds of formula I is one in which Rl and R 3 are aryl, R 2 and R 4 are hydrogen, Y is S(O)uR 8 or OR 9 Z is -(O)y-(CR 5
R
6 )s-RlO, R 7 is hydroxy, R 8 is lower alkyl, R 9 is hydrogen and R 10 is -COR 7 Another most preferred group of compounds of formula I is one in which R 1 and R 3 are aryl, R 2 and R 4 are hydrogen, X is 0, z is zero, t is 1, n is 3-5, Y is S(O)uR 8 or OR 9 Z is
(CR
5
R
6 )S-RlO, y is zero, s is 2-6, R 7 is hydroxy, R 8 is lower alkyl, R 9 is hydrogen and RIO is -COR 7 Most preferred examples of this invention are: 2-(3 -Carboxypropoxy)-6-[6-[(4,6-diphenyl-2-pyridinyl)oxy]hexyl]benzenepropanoic acid 2- [6-[(4,6-Diphenyl-2-pyridinyl)oxy] hexyl] hydroxy-4-methylpentyl)oxylbenzenepropanoic acid 2- [6-[(4,6-Diphenyl-2-pyridinyl)uxy] hexyl]-6-[4'-(methylsulfonyl)butoxylbenzenepropanoic acid 4- [6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyll hvdroxy-3 -methylbutyl)phenoxyllbutanoic acid 3-(2-Carboxyethyl)-44'6-[(4,6-diphenyl-2-pyridinyl)oxyljhexyl]-benzeneperitanoic acid 5-(3-Carboxypropoxy)-2- [6-[(4,6-diphenyl-2-pyridinyl)oxylhexyllbenzenepropanoic acid.
Other preferred examples include: 2-[3 -(2-Carboxyphenyl)propoxy] -6-[6-[(4,6-diphenyl-2pyridinyl)oxylhexylllbeiizenepropanoic acid 2-[3 -(3-Carboxyphenyl)propoxy-6-116-[(4,6-diphenyl-2pyridinyl)oxylhexyl]benzenepropanoic acid WO 95/28386 I'CT/EP9/O 1262 -6 2-(3 -Carboxypropoxy)-6- [5 -dip hen yl-2-pyridi nyI) oxylpentyloxylbenzenepropanoic acid 2-(3-Carboxypropoxy)-6-[6-[(4-phenyl-6-(4-fluorophenyl)-2-pyridinyl)oxylhexyllbenzenepropanoic acid 2-(3-Carboxypropoxy)-6-[6-[(4-phenyl-6-(2-thienyl)-2pyridinyl)oxylhexyllbenzenepropanoic acid 2-[(4-Carboxyphenyl)methoxy] ,6-diphenyl-2pyridinyl)oxylhexyllbenzenepropanoic acid 2-[(2-Carboxyphenyl)methoxy] [6-[(4,6-diphenyl-2pyridinyl)oxylhexyllbenzenepropanoic acid 2- -Carboxyphe-iyl)methoxy] [(4,6-diphen yl-2pyridinyl)oxy] hexyl] bcnzenepropanoic acid.
Compounds of general formula I as well as their pharmaceutically acceptable salts can be manufactured in accordance with the, invention by a) reacting a compound of the general formula
R
3 a S -S 4 a aR 1-2 awherein L is a leaving group, RI, R 2 p\ 3
R
4
R
5
R
6 X, m, n, z and t are as previously defined and Y' and Z' are as ~BIIY~BBBi~;rsP~n~9iaa~a~a~ -7previously defined with the proviso that in any COR 7
R
7 is lower alkoxy, or b) saponifying a compound of the general formula I, wherein Y and/or Z contain(s) a -COR 7 group and R 7 is lower alkyl to mono- or di-acid derivatives, or c) reacting a compound of the general formula I, wherein the group(s) Y and/or Z contain(s) the group -COOH, with an arnin of the formula
H-NR
5
R
13 wherein R 5 is as defined above and R 13 is hydrogen, lower alkyl or a group -SO 2
R
8 and R 8 is as previously described, to the corresponding mono- or disubstituted amides or sulfonamides, d) reacting a compound of the general formula I, wherein Yis -CN with a metal azide to give a compound of the formula I, wherein Y is 20 and e) if desired, converting a compound of the general formula I into a pharmaceutically acceptable salt.
Further, the compounds of formula I can be prepared as 25 hereinafter described in Reaction Schemes 1-5 in more detail.
s~ *~4aC-~~'liB~3 WO 95/28386 PCT/E P95/01262 -8 Reaction Scheme 1
R
3 (X)X(CRR 6 )ny' R' 0 L(CH 2 )M(O)z
H
1-1 1-2 Bal R2 R R 4(X)X(CR
R%)Y'
R' N 0-(CH 2 )m (O)z la MOj R2 R3 R
(X)
1
(CR
5
R
6
R
1 'N 0- (CH 2 )m (OXlb wherein L is a leaving group, M is an alkali metal cation, R 1
R
2
R
3
R
4
R
5
R
6 X, m, n, z, and t are as previously defined. Y' is Y as previously defined with the proviso that any COR 7 are COR 7 wherein R 7 is lower alkoxy. Y" is Y as previously defined with the provisos that any COR 7 are COR~
T
wherein RT' is hydroxy, and any R9areR9 wherein R 9 is hydrogen. Z' is Z as previously defined with the proviso that any GOR 7 are COR wherein R 7 is lower alkoxy. Z" is Z as previously defined with the WO 95/28386 PCT/EP95/01262 -9provisos that any COR 7 are COR7" wherein R 7 is hydroxy, and any R9 are R 9 wherein R 9 is hydrogen.
In Reaction Scheme I, the pyridone of formula 1-1 is alkylated with a compound of formula 1-2 giving the product of formula Ia. This alkylation is carried out in the presence of a base, and in an inert solvent. Among the preferred bases utilized in this alkylation reaction are alkali metal carbonates such as sodium or potassium carbonate, or transition metal carbonates such as silver carbonate. Preferred inert solvents for carrying out this alkylation are toluene and N,N-dimethylformamide. It is preferred that this alkylation be carried out within a temperature range of from 80 to 120 0 C. The compound of formula Ia can be recovered by conventional chromatography. Saponification of the compound of formula Ia, which can contain one or two ester functions, is carried out under standard conditions for the saponification of esters, giving the corresponding mono- or diacid of formula Ib. For example, this saponification can be carried out using an alkali metal hydroxide, such as sodium, potassium, or lithium hydroxide, in a lower alkanol solvent such as methanol or ethanol, within a temperature range of from 60 to 80 oC. The acid of formula Ib is recovered by recrystallization.
Exemplary of known intermediates of formula 1-1 are the following which are prepared as described in Journal of Medicinal Chemistry, Vol. 35, pp. 4315-4324, 1992: 4,6-Diphenyl-2-pyridone, 4-(3-Methoxyphenyl)-6-phenyl-2-pyridone, 4-(2-Fluorophenyl)-6-phenyl-2-pyridone, 6-(4-Fluorophenyl)-4-phenyl-2-pyridone, and 6-(4-Methylphenyl)-4-phenyl-2-pyridone.
I WO 95/28386 PCT/,EP95/01262 10 Other examples of known intermediates of formula 1-1 are: 4,6 -Diphenyl-5 -methyl-2-pyrid one, prepared as described in Tetrahedron Letters, Volume 29, pp. 4855-4858, 1988, 6-tert.-Butyl-4-phenyl-2-pyridone and 4 -Phenyl- 6-(2-thienyl) -2-pyrid one both prepared as described in International Patent Application WO 92/01675, 4,6-Diphenyl-5-methoxy-2-pyridone prepared as described in J. Chem. Soc., pp. 2588-2594, 1959, and 5-Bromo-4,6-diphenyl-2-pyridone prepared as described in An. Quim., Vol. 75, pp. 124-127, 1979.
Exemplary of known intermediates of formula 1-2 are the following which are prepared as described in U.S. Patent No.
5,273,999: 5-(4-ethoxy-4oxobutoxy)benzenepropanoic acid ethyl ester 2-[6-[(Methylsulfonyl)oxyllhexyl]-5-(4-methoxy-4oxobutoxy)-benzenepropanoic acid methyl ester 6-(5-Ethoxy-5-oxopentyloxy)-2-[[5-[(methylsulfonyl)oxy] pen tyll oxyl benzenepropanoic acid methyl ester 4- [(5-Bromopentyl)oxy] -ethoxy-3-oxopropyl)-8oxobenzenepentanoic acid ethyl ester 4- -Bromopentyl)oxy] -3 -ethoxy-3 -oxopropyl)-yoxobenzene-butanoic acid ethyl ester (E)-4-[3-(3-Methoxy-3 -oxo-l1-propenyl)-4- [6-[(methylsulfonyl)oxyljhexyllphenoxylbutanoic acid methyl ester 2-(5-Methoxy-5-oxopentyloxy)-6-[6-[(methylsulfonyl)oxyjhexyl]benzenepropanoic acid methyl ester [(Methylsulfonyl)oxyllpentyl] oxy] -4-(4-methoxy-4oxobutoxy)benzenepropanoic acid methyl ester 2-(2-Methoxy-2-oxoethoxy)-6- [(methylsulfonyl)oxy]hexyl]-benzenepropanoic acid methyl ester WO 95/28386 PCT/EP95/01262 11 2- [(6-Methoxy-6-oxohexyl)oxy] -6-j16-[(methylsulfonyl)oxyihexyl] benzenepropanoic acid methyl ester 4- [[5-II(Methylsulfonyl)oxyllpentyl] oxy] 1,3 -benzenedipropanoic acid dimethyl ester 2-(3-Methoxy-3-oxopropyl)-3-116-[(methylsuifonyl)oxyllhexyl]benzenehexanoic acid methyl ester 2 [(4,4-Dimethyl-5 -methoxy-5 -ox open tyl) oxy] [6 [(methyl-sulfonyl)oxylhexyllbenzenepropanoic acid methyl ester 2-[[5-(Acetyloxy)pentylloxy] -6-[6-[(methylsulfonyl)oxy]hexyl] benzeneproparoic acid methyl ester 2-[(8-Methoxy-8-oxooctyl)oxy] [(methylsulfonyl)oxylhexyl]benzenepropanoic acid r.iethyl ester 2- [(9-Methoxy-9-oxononyi)oxy] [(methylsulfonyl)oxy] hexyl] benzenepropanoic acid methyl ester 2-(4-Methoxy-4-oxobutoxy)-6-[6-[(methylsuilfonyl)oxy] hexyllbenzenepropanoic acid methyl ester 4-(6-Bromohexyl)-3 -(3-ethoxy-3 -oxopropyl)-Soxobenzenepentanoic acid ethyl ester 4 -(5-Bromopentyloxy)-3-(3-ethoxy-3-oxopropyl)b--nzenepentanoic acid ethyl ester 4-(6 -B romohexyl)-3 -ethoxy-3 -ox opropyl) benzenepentanoic acid ethyl ester 2-[(7-Methoxy-7-oxoheptyl)oxy]-6-[6- [(methylsulfonyl)oxy] hexyl] benzenepropanoic acid methyl ester.
WO 95/28386 PCT/EP95/01262 12 Reaction Scheme 2
OH
L(CH
2 O Base
OH
R"O(CH
2
CORR
5
R
6 2-1 2-2 0- (CH 2 SR6 OH H 2 Catalyst
R"O(CH
2 )q 2 COR
T
2-3 0- (CH)r 2 O- (CH)+2OH
SR"OCOR
7 H
COR
2-4 0- (CH 2 )r+ 2
R
5
R
6 L(CHq+2 COR 2-6 wherein, R 5
R
6 and L are as previously defined, R 7 is lower alkoxy, R 1 1 is an acid sensitive hydroxyl protecting group, and q and r are, independently, an integer from 1-10.
In Reaction Scheme 2, a phenol of formula 2-1, which represents known compounds prepared as described in U.S.
Patent No. 5,273,999, is alkylated with a compound of formula 2-2, which represents known compounds or compounds which can be prepared by known methods, in the presence of a base, to give a product of formula 2-3 which is recovered by standard chromatographic methods. This alkylation reaction is preferably carried out using an alkali metal carbonate such as ~_s~PI~_I WO 95/28386 PCTIEP95/01262 13 sodium or potassium carbonate as the base, within a temperature range of from about 25 OC. to about 110 0 in a polar, aprotic solvent such as acetonitrile, N,N-dimethylformamide, 2-butanone, or dimethyl sulfoxide. Catalytic hydrogenation of the compound of formula 2-3 gives the product of formula 2-4 which is recovered by chromatography. It is preferred that this hydrogenation be carried out using palladium on carbon as the catalyst, and ethyl acetate as the solvent. The compound of formula 2-4 is converted to the compound of formula 2-5 using conditions generally employed for the removal of acid sensitive hydroxyl protecting groups.
For example, the compound of formula 2-4 can be treated with an acid in a lower alkanol solvent. It is preferred that this deprotection reaction be carried out using oxalic acid in aqueous metharol, within a temperature range of from about 250C to about 65 oC. The product of formula 2-5 is recovered by chromatography and is converted to the corresponding derivative 2-6 using standard methods known in the art for transforming hydroxy groups into leaving groups. These methods include treatment with halogenating reagents such as N-bromosuccinimide/triphenylphosphine or iodine/triphenyl.
phosphine in dichloromethane. Alternatively, the compound of formula 2-5 can be converted to the corresponding sulfonate of formula 2-6 by conventional methods such as treatment with an arylsulfonyl chloride and an organic amine. These sulfonic esters can, in turn, be converted into the corresponding iodides of formula 2-6 by treatme-t with an alkali metal iodide in a polar, aprotic solvent. It is preferred that this conversion be carried out using sodium iodide, in acetonitrile, within a temperature range of 20-80 oC. The compounds of formula 2-6 are recovered by conventional extractive work-up.
~a~WsRare~Oir~aerasnreas~ WO 95/28386 PCTIEP95/01262 14 Reaction Scheme 3
OH
L(C ase Sj R"O(CH,) q COR .1 2-1 H Caulyst O Acid
R"O(CH
2 q CORT
CORT
3-2 3-3 O(CH')Y O(CHr
HO(CH,)
2 L( CH),3,
COR
T
COR
7 3.4 3-S wherein L, R 7
R
11 n, and q are as previously defined.
In Reaction Scheme 3, a phenol of formula 2-1 is alkylated with a compound of formula 3-1, which represents known compounds or compounds which can be prepared by known methods, in the presence of a base, to give a product of formula 3-2 which is recovered by standard chromatographic methods.
This alkylation reaction is carried out as described in Reaction Scheme 2 for the conversion of the compound of formula 2-1 to the compound of formula 2-3. Catalytic hydrogenation of the compound of formula 3-2 is carried out as described in Reaction Scheme 2 for the conversion of the compound of formula 2-3 to the compound of formula 2-4. The deprotection of the compound of formula 3-3 to give the alcohol product of formula 3-4 is carried out as described in Reaction Scheme 2 for the conversion of the compound of formula 2-4 to the compound of formula 2-5. The compound of formula 3-4 is transformed into the compound of formula 3-5 as described in Reaction Scheme 2 i ~IB~BPaarsaaasr ;~aaarr~wra~arersra- WO 95/28386 PCT/EP95/01262 15 for the conversion of the compound of formula 2-5 to the compound of formula 2-6.
Reaction Scheme 4
OH
H2, CatlyL R"O(CH)q
COR
7 2-1
OH
Acid R"1O(CH~p- COR
T
OH
HO(CH2)
COR
7
^^CORT
RrM 4-3
L(CHACOR
T
,OH
.OH
HO(CHO)
2 L(CH) wherein R 5 is lower alkyl, M' is lithium or halomagnesium, and L, R 7 R 1, n, and q are defined.
as previously In Reaction Scheme 4, a phenol of formula 2-1 is catalytically hydrogenated to give the corresponding reduced compound of formula 4-1 as described in Reaction Scheme 2 for the conversion of the compound of formula 2-3 to the compound of formula 2-4. The deprotection of the compound of formula 4-1 to give the alcohol product of formula 4-2 is carried out as described in Reaction Scheme 2 for the conversion of the compound of formula 2-4 to the compound of formula Reaction of the compound of formula 4-2 with an excess of the organometallic reagent of formula 4-3, which represents known 111 Ill~ara~PII lus~-m~ -r~-Yli~ l aslpP WO 95/28386 PCT/EP95/01262 16 compounds, gives the triol of formula 4-4. It is preferred that the reagent 4-3 be a Grignard or organolithium reagent and that this reaction be carried out in an inert solvent such as ether or tetrahydrofuran, within a temperature range of from 0°C to about 65 0 C. The product of formula 4-4 is recovered by chromatography. Alkylation of the compound of formula 4-4 with a compound of formula 4-5, which represents known compounds, is carried out as described in Reaction Scheme 2 for the conversion of the compound of formula 2-1 to the compound of formula 2-3, and gives the compound of formula 4-6, which is recovered by chromatography. The compound of formula 4-6 is transformed into the compound of formula 4-7 as described in Reaction Scheme 2 for the conversion of the compound of formula 2-5 to the compound of formula 2-6.
WO 95/28386 Wo 9528386PCTIE P95/01262 17 Reaction Scheme (X)t(CR 5
R
6 )ny" (C H 2 )m(0)z H-NRSR 1 3 0-(CH 2 )m ,(O)zC El
IC
R
2 R3 R4()(RR nN M"(N3)k
R
1 N 0-
MOH
k3 (XXt(CRR 6) N=N
R
1 N 0-(CH 2 )mn-(O)rC)if wherein M, Rl, R 2
R
3
R
4
R
5
R
6 X, m, n, z, and t are as previously defined and is Y as previously WO 95/28386 PCT/EP95/01262 18 defined with the proviso that any COR 7 is COR 7 wherein
R
7 is NR 5
R
6 is Z as previously defined with the proviso that any COR 7 is COR 7 wherein R 7 is NR 5
R
6 R13 is hydrogen, lower alkyl, or S02R 8 wherein R 8 is as previously defined, M" is sodium, lithium, aluminum, magnesium, or tri(lower alkyl)stannyl, and k is an integer from 1 to 3 depending on the valence of M".
In Reaction Scheme 5, an acid of formula Ib (Reaction Scheme 1) is converted to the corresponding amide or acylsulfonamide of formula Ic by reaction with the amine or sulfonamide R 5
R
13 NH, which represents known compounds.
This reaction can be carried out using any of the standard methods of forming amides or acylsulfonamides from acids.
These include treatment of the acid with 1,1'-carbonyldiimidazole and the amine or exposure of the acid to a base, a carbodiimide and the amine or sulfonamide. It is understood that if more than one carboxyl moiety is present in t, starting acid, all such groups will be converted to the correspnon;ig amide or acylsulfonamide linkage. It is preferred that the reaction be performed by treating the acid of formula Ib with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 4-dimethylaminopyridine, and the amine or sulfonamide R 5
R
13 NH, in dichloromethane solution, at ambient temperature. The amide or acylsulfonamide of formula Ic is recovered by chromatography or recrystallization.
Treatment of the nitrile of formula Id, which can be prepared as described in Reaction Schemes 1 and 3, with a metal azide M"(N3)k, which represents known compounds, gives the tetrazole of formula Ie, which is recovered by chromatography or recrystallization. This reaction can be carried out using any of the common azide reagents including sodium azide, lithium azide, magnesium azide, aluminum azide, and tri(lower alkyl)stannyl azides. It is preferred that this 9- Bl~fl~RS~fi~wrrarraaarp~R PCT/EP95/01262 WO 95/28386 19 reaction be carried out using tri(n-butyl)stannyl azide in dioxane solution, within a temperature range of from about 80 0
C
to about 100 0 C. Saponification of the ester Ie is carried out as described in Reaction Scheme 1 for the conversion of the compound of formula la to the compound of formula Ib, giving the tetrazole acid of formula If which is recovered by chromatography or recrystallization.
Reaction Scheme 6 L- (CH 2 )n
COR
T Base R"O(CH2)q42'
COR
T
(CH2)n COR T Acid-
RO
1 0(CH2)q+2 R
COR
6-2 COR7 -I HO(CH2)q+2
'COR
7 wherein L, R 7
R
1 n, and q are as previously defined.
-a p~ ~C1 RI I~Pl~pLU1~--"~ WO 95/28386 PCTIEP95/01262 20 In Reaction Scheme 6, a phenol of formula 4-1 is alkylated with a compound of formula 6-1, which represents known compounds or compounds which can be prepared by known methods, in the presence of a base, to give a product of formula 6-2 which is recovered by standard chromatographic methods.
This alkylation reaction is carried out as described in Reaction Scheme 2 for the conversion of the compound of formula 2-1 to the compound of formula 2-3. Deprotection of the compound of formula 6-2 to give the alcohol product of formula 6-3 is carried out as described in Reaction Scheme 2 for the conversion of the compound of formula 2-4 to the compound of formula 2-5. The compound of formula 6-3 is transformed into the compound of formula 6-4 as described in Reaction Scheme 2 for the conversion of the compound of formula 2-5 to the compound of formula 2-6.
l Is M WO 5/2386PCTfEPP95/O 1262 WO 95/28386 21 Reaction Scheme 7 HO (CH 2 I COR7 Ar 3
P
f-
R
7 O0 2
CN=NCO
2 R7
COR
T
0- (CH 2 )v
H
2 catalyst
CORT
R
1 1 (CH2)q COR 7 7-2 0- (CH 2 )v Acid
COR
T
R1O(CH 2 )q CR
COR
T
HO(CH2)q+2V COR7T wherein L, RT, R 11 q, and v are as previously defined, and Ar is aryl.
In Reaction Scheme 7, a phenol of formula 2-1 is condensed with a compound of formula 7-1, which represents known compounds or compounds which can be prepared by known methods, in the presence of a phosphine and an azodicarboxylic WO 95/28386 PCT/EM95/(1262 22 diester, to give a product of formula 7-2 which is recovered by standard chromatographic methods. Among the preferred phosphines which can be employed in this condensation are triaryl phosphines such as triphenylphosphine. Among the preferred azodicarboxylic diesters which can be employed in this condensation are lower alkyl azodicarboxylic diesters such as diethyl azodicarboxylate. It is preferred that this condensation be carried out in an inert, ether solvent such as diethyl ether or tetrahydrofuran within a temperature range of 25-75 oC.
Catalytic hydrogenation of the compound of formula 7-2 to give the corresponding saturated compound 7-3 is carried out as described in Reaction Scheme 2 for the conversion of the compound of formula 2-3 to the compound of formula 2-4.
Deprotection of the compound of formula 7-3 to give the alcohol product of formula 7-4 is carried out as described in Reaction Scheme 2 for the conversion of the compound of formula 2-4 to the compound of formula 2-5. The compound of formula 7-4 is transformed into the compound of formula 7-5 as described in Reaction Scheme 2 for the conversion of the compound of formula 2-5 to the compound of formula 2-6.
'I WO 95/28386 CI9IO16 PCT/tIP95/01262 23 Reaction Scheme 8
L(CH
2 ).COR 7 Base -N I O(CH,)COR 7 0 0 S,,7 8-2 I O(CHACOR!
HO
cR? 8.3 L(CH2),L I O(CHiACOR 7 L(CH2)XO Base cR 7
&OR
7 8-6
H
2 jI CalYSt O(CI-b).COR 7
.COR
7 wherein R 2
R
3 R R 7 L, M, n and v are as previously defined.
IIIIII~BE~(P~R&~s~l~aBa~' WO 95/28386 PCT
P
95/01262 24 In Reaction Scheme 8, alkylation of a coumarin of formula 8-1, which represents compounds known in the art, with an ester of formula 4-5, which also represents compounds known in the art, in the presence of a base, gives the product of formula 8-2.
This alkylation is carried out under standard conditions for effecting the alkylation of a phenol such as those described in Reaction Scheme 2 for the conversion of the compound of formula 2-1 to the compound of formula 2-3. The compound of formula 8-2 is recovered by conventional chromatographic methods and is converted to the corresponding 2-hydroxycinnamate of formula 8-3 by alcoholysis of the lactone ring using an alkali metal lower alkoxide in a lower alkanol solvent. This transformation is carried out using lithium, sodium, or potassium lower alkoxide. It is preferred that this transformation be carried out in methanol or ethanol with sodium methoxide or sodium ethoxide, at a temperature in the range of 60-120 oC. The compound of formula 8-3 is recovered by standard chromatographic methods. Alkylation of the compound of formula 8-3 with a compound of formula 8-4, which represents known compounds such as 1,5-dibromopentane, 1-bromo-3-chloropropane and the like, is carried out as described in Reaction Scheme 2 for the conversion of the compound of formula 2-1 to the compound of formula 2-3, and affords the compound of formula 8-5 which is recovered by chromatography. Alkylation of the pyridone of formula 1-1 with the compound of formula 8is carried out as described in Reaction Scheme 1 for the conversion of the compound of formula I-1 to the compound of formula Ia, and gives the compound of formula 8-6, which is recovered by chromatography. Catalytic hydrogenation of the compound of formula 8-6 using the procedure described in Reaction Scheme 3 for the conversion of the compound of formula 3-2 to the compound of formula 3-3, gives the corresponding saturated compound of formula 8-7, a sub-species of Ia.
I- Ilci- I WO 95/28386 PCT/EP95/11262 25 The invention also relates to a salt of the compound of formula I when it contains an acidic functionality which lends itself to salt formation with a base. Salts of compounds of formula I whici have a carboxy group are prepared by the reaction with a base having a non-toxic, pharmacologically acceptable cation. In general, any base which will form a salt with a carboxylic acid and whose pharmacological properties will not cause an adverse physiological effect is within the scope of this invention.
Suitable bases thus include, for example, the alkr'i metal and alkaline earth metal hydroxides, carbonates or the like, for example, calcium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate c the like, ammonia, primary, secondary and tertiary amines, such as, monoalkylamines, dialkylamines, trialkylamines, for example, methylamine, diethylamine, triethylamine or the like, nitrogen containing heterocyclic amines, for example, piperidine or the like. A salt thus produced is the functional equivalent of the corresponding compound of formula I wherein R 7 is hydroxy and one skilled in the art will appreciate that the variety of salts embraced by the invention is limited only by the criterion that a base employed in forming the corresponding salts be both non-toxic and physiologically acceptable.
The useful activity of the compounds of formula I as leukotriene B4 antagonists can be demonstrated as hereinafter set forth.
Guinea Pig Bronchoconstriction In Vivo.
Male guinea pigs (Hartley strain) weighing 300 to 500 g are anesthetized with urethane (2g/kg) intraperitoneally and a polyethylene cannula is inserted into the jugular vein for drug administration. Tracheal pressure is recorded from a cannula "C*lb I~Dae(l)-~P RIIP3 ~a~Y~~OIRlr~ I~~ WO 95/28386 PCT/EP95/01262 26 inserted into the trachea and connected to a Gould P23ID pressure transducer. After surgical preparation of the animals, a period of time is allowed for pulmonary functions to stabilize.
The test compound is administered orally 2 hours prior to leukotriene B4 administration according to the following protocol: Animals are paralyzed with succinylcholine (1.2 mg/kg and mechanically respirated (Harvard rodent respirator) at 40 breaths/minute and 2.5 cc tidal volume.
Propranolol (0.1 mg/kg) is then administered intravenously five minutes prior to leukotriene B4 administration. Animals are then challenged with an intermediate constrictory dose of leukotriene B4 (200 lg/kg) delivered intravenously.
The change (cm H20) between pre and peak ventilatory pressure readings is averaged for six control and six drug treated animals. The percent inhibition is calculated from the formula: ((Control Drug Treated)/Control)x100 When compounds of formula I were tested, the percent inhibition of a 0.1 mg/kg oral dose was as follows.
WO 95/28386 VCIVE,1195/01262 27 inhibition, 0.1 mg/kg test compound dose 2-(3-Carboxypropoxy)-6-[6-[(4,6-diphenyl- 8 6 2-pyridinyl)oxy]hexyllbenzenepropanoic acid 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxylhexyl]-6- 27 [(4-hydroxy-4-methylpentyl)oxy] benzenepropanoic acid 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxyl. -xyl] [4-(methylsulfonyl)butoxyllbenzenepropanoic acid 4-[3-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl] 4 1 (3-hydroxy-3 -methylbutyl)phenoxylbutanoic acid 5-(3-Carboxypropoxy)-2-[6-[(4,6-diphenyl-2- pyridinyl)oxylhexyllbenzenepropanoic acid 2-[3-(2-Carboxyphenyl)propoxy] 5 6 diphenyl-2-pyridinyl)oxy]hexylj benzenepropanoic acid 2- [3-(3-Carboxyphenyl)propoxy] diphenyl-2-pyridinyl)o7,ylhexyllbenzenepropanoic acid 2-(3-Carboxypropoxy)-6-II[5-[(4,6-diphenyl-2- 62 pyridinyl)oxylpentylloxy]benzenepropanoic acid 2-(3-Carboxypropoxy)-6-[6-[[6-(4-fluorophenyl)- 6 8 4-phenyl-2-pyridinyl] oxy] hexyllbenzenepropanoic acid WO 95/28386 PCT/EP95/01262 28 2-(3-Carboxypropoxy)-6-[6-[[4-phenyl-6- (2-thienyl)-2-pyridinyl]oxy]hexyl]benzenepropanoic acid 2-[(4-Carboxyphenyl)methoxy]-6-[6-[(4,6- 42 diphenyl-2-pyridinyl)oxy]hexyl]benzenepropanoic acid 2-[(2-Carboxyphenyl)methoxy]-6-[6-[(4,6- diphenyl-2-pyridinyl)oxy]hexyl] benzenepropanoic Acid 2-[(3-Carboxyphenyl)methoxy]-6-[6-[(4,6- 42 diphenyl-2-pyridinyl)oxy]hexyl]benzenepropanoic Acid Isolation of Intact Neutrophils Human neutrophils are prepared from citrated or heparinized blood. The blood was diluted 1:1 with Hank's balanced salt solution (HBSS) minus calcium and magnesium and underlayed with 10 ml lymphocyte separation medium (Organon Teknika), followed by centrifugation at 500 x g for minutes, at room temperature. Supernatants are removed down to the red blood cell pellet. HBSS minus calcium and magnesium is added to give 25 ml. To this is added 25 ml 6% dextran in 0.85% NaCl. Samples are mixed and allowed to stand minutes at room temperature. Supernatants are removed and centrifuged at 500 x g for 5 minutes at 4 0 C. Pellets are resuspended with 20 ml 0.2% saline for 20 seconds followed by the addition of 20 ml 1.6% saline. Samples are centrifuged at 500 x g for 5 minutes at 4 0 C. The lysis is repeated and the cells (90-95% neutrophils) are resuspended at 2x10 6 cell/ml in GEY's salt solution.
I c WO 95/28386 PCT/EP95/01262 29 LTB4 Receptor Binding Assay Binding assays are performed in microtiter wells. Isolated human neutrophils in Gey's salt solution are incubated on ice for minutes with 0.5nM 3 H-LTB4 in the presence or absence of test compounds. Assays are terminated by adding 12 ml ice cold 50 mM Tris (pH 7.4) followed by rapid filtration under vacuum through GF/C filters. Radioactivity is determined by scintillation counting. Non- specific binding is defined as the binding not displaced by 100 fold excess of unlabelled LTB4.
Specific binding is defined as the difference between total binding and non-specific binding. Non linear analysis of the binding data is performed using LIGAND (Munson and Rodbard, 1980). Ki (Inhibition Constant) values were determined using the Cheng-Prusoff relationship (Cheng and Prusoff, 1973).
When representative compounds of formula I of the invention were tested, the results, as set forth below, expressed as inhibition of 3 H-LTB4 binding, were obtained.
2 0 HUMAN NEUTROPHIL TEST COMPOUND CELLS (KI nM) 2-(3-Carboxypropoxy)-6-[6-[(4,6-diphenyl- 2 1 pyridinyl)oxy]hexyl]benzenepropanoic acid 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6- [(4-hydroxy-4-methylpentyl)oxy]benzenepropanoic acid 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]- 6 [4-(methylsulfonyl)butoxy]benzenepropanoic acid 4-[3-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-2- (3-hydroxy-3-methylbutyl)phenoxy]butanoic acid 19 WO 95/?8386 MWEP95/01262 30 -Carboxypropoxy)-2-[6- [(4,6-diphenyl-2- 1 pyridinyl)oxyjhexyllbenzenepropanoic acid 2-[3-(2-Carboxyphenyl)propoxy-6-[6-1j(4,6- 1 diphenyl-2-pyridinyl)oxy] hexyll benzenepropanoic acid 2-(3-Carboxypropoxy)-6-[[5-[(4,6-diphenyl-2- 0.4 pyridinyl)oxy] pentyl] oxyl benzenepropan oic acid 2-(3-Carboxypropoxy)-6-[6-[[6-(4-fluorophenyl)- 0.2 4-phenyl -2-pyridinyl] oxy] hexyl] benzenepropanoic acid 2-(3-Carboxypropoxy)-6-[6-[[4-phenyl-6- 0.6 (2-thienyl)-2-pyridinyl] oxy] hexyl] benzenepropanoic acid 2- [(4-Carboxyphenyl)methoxy]-6-[6-j(4,6- 0.3 diphenyl-2-pyridinyl)oxy] hexyl] benzenepropanoic acid 2- [(2-Carboxyphenyl)methoxy]-6-[6- 0.2 diphenyl-2-pyridinyl)oxy] hexyl] benzenepropanoic acid 2-[(3-Carboxyphenyl)methoxy]-6-[6-[(4,6- 0.3 diphenyl-2-pyridinyl)oxy] hexyl] benzenepropanoic acid In the practice of the invention, the dose of a compound of formula I or a salt thereof to be administered and the frequency of administration will be dependent on the potency and duration of activity of the particular compoulA. of formula I or BIIYJsllllUIII" ll~ WO 95/28386 P'CT/EP95/01262 31 salt to be administered and on the route of administration, as well as the severity and nature of the condition and age of the mammal to be treated and the like. Oral doses of a compound of formula I or a salt thereof contemplated for use in practicing the invention can be in the range of from 2 mg to about 2 g per day, preferably about 2 mg to about 1 gm per day, either as a single dose or in divided doses.
A compound of formula I, or a salt or a composition containing a therapeutically effective amount of a compound of formula I, an enantiomer or a racemate or a salt thereof can be administered by methods well known in the art. Thus, a compound of formula I, or a salt thereof can be administered either singly or with other pharmaceutical agents, for example, antihistamines, mediator release inhibitors, methyl xanthines, beta agonists or antiasthmatic steroids such as prednisone and prednisolone, orally, parenterally, rectally, or by inhalation, for example in the form of an aerosol, micropulverized powder or nebulized solution. For oral administration they can be administered in the form of tablets, capsules, for example, in admixture with talc, starch, milk sugar or other inert ingredients, that is, pharmaceutically acceptable carriers, or in the form of aqueous solutions, suspensions, elixirs or aqueous alcoholic solutions, for example, in admixture with sugar or other sweetening agents, flavoring agents, colorants, thickeners and other conventional pharmaceutical excipients. For parenteral administration, they can be administered as solutions or suspension, for example, as an aqueous or peanut oil solution or suspension using excipients and carriers conventional for this mode of administration. For administration as aerosols, they can be dissolved in a suitable pharmaceutically acceptable solvent, for example, ethyl alcohol or combinations of miscible solvents, and mixed with a pharmaceutically acceptable propellant. Such aerosol compositions are packaged for use in pressurized container fitted with an aerosol valve suitable for c WO 95128386 PCT/EI'95/01262 32 release of the pressurized composition. Preferably, the aerosol valve is a metered valve, that is one which on activation releases a predetermined effective dose of the aerosol composition.
Since compounds of formula I of the invention may possess an asymmetric carbon atom, they are ordinarily obtained as racemic mixtures. It is to be understood the enantiomers and diastereomers also form part of this invention.
The resolution of such racemates into the optically active isomers can be carried out by known procedures. Some racemic mixtures can be precipitated as eutectics and can thereafter be separated. Chemical resolution is, however, preferred. By this method, diastereomers are formed from the racemic mixture of a compound of formula I, with an optically active resolving agent. The formed diastereomers are separated by selective crystallization or chromatography and converted to the corresponding optical isomer. Thus the invention covers the racemates of the compounds of formula I as well as their optically active isomers (enantiomers).
The examples which follow further illustrate the invention.
In the following examples, the "usual work-up" procedure involves three extractions with the specified solvent. The organic extracts were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under water aspirator pressure. The residue was dried to constant weight at 45°C/high vacuum. All reactions except hydrogenations were carried out under an inert atmosphere of nitrogen or argon.
I'
WO 95/28386 PCT[ P95/01262 33 Example 1 Preparation of 2-(6-Iodohexyl)-6-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester.
A mixture of 10.81 g (ca. 23.37 mmol) of crude 2-(4methoxy-4-oxobutoxy)-6-[6-[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester, 7.01 g (46.7 mmol) of anhydrous sodium iodide, and 44 mL of dry acetonitrile was stirred at room temperature for 17 hr and then refluxed for hr. After being cooled, the mixture was diluted with 200 mL of ether and filtered with suction. The solids were washed thoroughly with ether. The filtrate and washes were combined and washed with 12% aqueous sodium bisulfite, and work-up was completed in the usual manner. There was obtained 11.14 g of 2-(6-iodohexyl)-6-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester as a yellow oil.
Example 2 Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-(4methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester.
A mixture of 12.86 g (26.24 mmol) of 2-(6-iodohexyl)-6- (4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester, 6.18 g (25 mmol) of 4,6-diphenyl-2-pyridone, 3.45 g (12.51 mmol) of silver carbonate, and 250 mL of toluene was stirred and refluxed for 18 hr. After being cooled, the mixture was filtered with suction through a pad of Celite. The solid cake was washed well with toluene. The filtrate and washes were combined and concentrated in vacuo giving a yellow oil. This material was treated with 1 g (4.05 mmol) of the pyridone, 3.45 g (12.51 mmol) of fresh silver carbonate, and 250 mL of toluene. The mixture was stirred under reflux for an additional 2 hr and at room temperature for 16 hr. Work-up as before -a _I WO 95/28386 PCT/r, P95/01262 34 gave 17.96 g of an oily product. This material was chromatographed on silica gel, eluting with hexane-ethyl acetate mixtures. There was obtained 14.29 g of pure title dimethyl ester, as a viscous, amber oil.
Exar'ple 3 Preparation of 2-(3-Carboxypropoxy)-6-[6-[(4,6-diphenyl-2pyridinyl)oxy]hexyl]benzenepropanoic acid.
A mixture of 2-[6-[(4,6-diphenyl-2-pyridinyl)oxy]hexyl]- 6-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester (preceding example) (14.29 g; 23.46 mmol), 4.48 g (70.4 mmol) of potassium hydroxide, and 250 mL of methanol was stirred and refluxed, for 4.5 hr. The resulting pale-yellow solution was concentrated in vacuo to remove most of the solvent and the residue was dissolved in water and acidified with 1N aqueous hydrochloric acid. The mixture was worked-up with dichloromethane in the usual manner giving a viscous, yellow gum. Thin layer chromatographic and NMR spectral analysis of this product revealed that saponification was incomplete.
Therefore, this material was redissolved in 250 mL of methanol and 7.5 g (117.86 mmol) of potassium hydroxide was added.
The solution was stirred and refluxed for 21 hr before being concentrated in vacuo. The residual paste was taken up in 250 mL of water and the resulting milky solution was filtered with suction. The filtrate was acidified with 3N aqueous hydrochloric acid and worked-up with ether in the usual manner. There was obtained 13.18 g of a pale-yellow solid which was recrystallized from acetonitrile giving 12.48 g of the pure title diacid, as a colorless solid, mp 77-79 oC.
Anal. Calcd for C36H39N06: C, 74.33; H, 6.76; N, 2.41.
Found: C, 74.14; H, 6.64; N, 2.40.
I -C II WO 95/28386 PCT/EP195/01262 35 Example 4 Preparation of rac-(E)-3-[2-[(4-Hydroxy-4-methyl-2-pentynyl)oxy] -6-[6-[(tetrahydro-2H-pyran-2-yl)oxy] -1 -hexynyl]phenyl] 2-propenoic acid methyl ester.
A mixture of 1.08 g (6.11 mmol) of 5-bromo-2-methyl-3pentyn-2-ol, 2.19 g (6.11 mmol) of rac-(E)-3-[2-hydroxy-6-[6- [(tetrahydro-2H-pyran-2-yl)oxy] -1 -hexynyl]phenyl] -2propenoic acid methyl ester, 3.38 g (24.45 mmol) of anhydrous, granular potassium carbonate in 50 mL of 2-butanone was stirred and heated at reflux for 5.33 hr. Another portion of bromo-2-methyi-3-pentyn-2-ol (0.17 g; 0.94 mmol) and 10 mL of 2-butanone were added and the reaction was allowed to proceed for another 17.33 hr. After being cooled to room temperature, the mixture was filtered through some anhydroas magnesium sulfate and the solids were washed thoroughly with ethyl acetate. The filtrate and the washings were combined and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate to afford 2.52 g of the title compound as a yellow oil.
Anal. Calcd for C27H3406: C, 71.34; H, 7.54. Found: C, 71.31; H, 7.36.
Example Preparation of rac-2-[(4-Hydroxy-4-methylpentyl)oxy-6-[6- [(tetrahydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester.
To a solution of 2.4 g (5.28 mmol) of hydroxy-4-methyl-2-pentynyl)oxy-6-[6-[(tetrahydro-2Hpyran-2-yl)oxy]-1 -hexynyllphenyl] -2-propenoic acid methyl ester in 100 mL of ethyl acetate was added 1.0 g of 10% Pd/C c WO 95/28386 PCT/EP95/01262 36 and the mixture was hydrogenated at atmospheric pressure and room temperature overnight. The mixture was filtered through a pad of celite, and the solids were washed thoroughly with ethyl acetate. After removal of the solvent, the crude product was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate to afford 2.01 g of the title compound as a colorless oil.
Anal. Calcd for C27H4406: C, 69.79; H, 9.55. Found: C, 69.98; H, 9.40.
Example 6 Preparation of 2-(6-Hydroxyhexyl)-6-[(4-hydroxy-4methylpentyl)oxy]benzenepropanoic acid methyl ester.
To a solution of 2.0 g (4.3 mmol) of rac-2-[(4-hydroxy-4methylpentyl)oxy]-6-[6-[(tetrahydro-2H-pyran-2yl)oxy]hexyl]-benzenepropanoic acid methyl ester in 75 mL of methanol were added 10 mL of water and 2.0 g (15.86 mmol) of oxalic acid dihydrate and the resulting solution was stirred at room temperature for 17 hr. Most of the methanol was removed under reduced pressure and the residue was taken up in ethyl acetate. The ethyl acetate solution was then washed twice with water. After completion of the usual workup, the crude product was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (2:1 then 1:1) to give 1.40 g of the title compound as a pale yellow oil.
Anal. Calcd for C22H3605: C, 69.44; H, 9.54. Found: C, 69.22; H, 9.51.
WO 95/28386 11CIVE1195/012()12 2 37 Example 7 Preparation of 2-(6-Bromohexyl)-6-[(4-hydroxy-4-methylpentyl)oxy]benzenepropanoic acid methyl ester.
To a mixture of 1.36 g (3.56 mmol) of 2-(6-hydroxyhexyl)-6-[(4-hydroxy-4-methylpentyl)oxy]benzenepropanoic acid methyl ester, 1.77 g (5.34 mmol) of carbon tetrabromide and 1.40 g (5.34 mmol) of triphenylphosphine was added 75 mL of ether and the resulting mixture was stirred at room temperature for 24 hr. Additional portions of carbon tetrabromide (1.77 g; 5.34 mmol) and triphenylphosphine (1.40 g; 5.34 mmol) were added and the reaction was allowed to proceed for another 17.25 hr. The mixture was filtered through anhydrous magnesium sulfate, and the solids were washed thoroughly with ether. After the usual workup, the crude product was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate to give 1.04 g (65.5 of the title compound as a colorless oil.
Anal. Calcd for C22H35BrO4: C, 59.59; H, 7.96; Br, 18.02.
Found: C, 59.66; H, 8.14; Br, 17.77.
Example 8 Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6- [(4-hydroxy-4-methylpentyl)oxy]benzenepropanoic acid methyl ester.
A mixture of 0.29 g (1.17 mmol) of 4,6-diphenyl-2pyridone, 0.52 g (1.17 mmol) of 2-(6-bromohexyl)-6-[(4hydroxy-4-methylpentyl)oxy]benzenepropanoic acid methyl ester, 0.33 g (1.19 mmol) of silver carbonate and 40 mL of toluene was stirred and refluxed, with protection from light by aluminum foil, for 46.2 hr. The mixture was cooled to room temperature, filtered through some anhydrous magnesium I- WO 95/28386 PCT/EP95/0262 38 sulfate, and the solids were washed with et,,l acetate. After concentrating the combined filtrate and washes, the crude product was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate to afford 0.60 g (84.7%) of the title compound as a light tan oil.
Anal. Calcd for C39H47N05: C, 76.82; H, 7.77; N, 2.30.
Found: C, 76.63; H, 7.71; N, 2.30.
Example 9 Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6- [(4-hydroxy-4-methylpentyl)oxy]benzenepropanoic acid.
To a mixture of 0.60 g (0.99 mmol) of 2-[6-[(4,6-diphenyl- 2-pyridinyl)oxy]hexyl]-6-[(4-hydroxy-4-methylpentyl)oxy]benzene-propanoic acid methyl ester in 13 mL of THF and 13 mL of water was added 85.0 mg (2.03 mmol) of lithium hydroxide monohydrate and the resulting mixture was stirred at room temperature for 42.5 hr. The solution was acidified with the addition of 25 mL of 3N sulfuric acid solution, and the resulting mixture was worked-up with ethyl acetate in the usual manner. The crude product was recrystallized from hexane-ethyl acetate to give 0.51 g of the title compound as a white solid, mp 83-84.5 oC.
Anal. Calcd for C38H45N05: C, 76.61; H, 7.61; N, 2.35.
Found: C, 76.60; H, 7.76; N, 2.24.
Example Preparation of rac-(E)-3-[2-[4-(Methylsulfonyl)butoxy]-6-[6- [(tetrahydro-2P .pyran-2-yl)oxy]-l-hexynyl]phenyl]-2propenoic acid methyl ester.
Starting with 1.16 g (3.23 mmol) of rac-(E)-3-[2-hydroxy- 6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-l-hexynyl]phenyl]-2- I II I u WO 9S/28386 11c"JIMP"(195/0 1262 -39 Sropenoic acid methyl ester and 0.71 g (3.30 mmol) of 4- (meth,,lsul.fonyl)butyl bromide, the title cor.ipound (1.39 g; 87.4%) was obtained ,s a white solid, mp 42-43 OC, following the procedure of Example 4.
Anal. Calcd for C26H3607S: C, 63.39; H, 7.37; S, 6.51.
Found: C, 63.25; H, 7.20; 8, 6.50.
E- Jamplo 1 Preparation of rac-2-[4-(Methylsulfonyl)butoxy-6-16- [(tetrahydro-2H-pyran-2-yl)oxy] hexyl] benzene;-,-ropanoic Acid Methyl Ester.
Starting with 1.33 g (2.71 mmol) of 1 5 lemethylsnilfonyl)butoxy] -6-[6-[(tetrahydro-21. -pyran-2-yl)oxy] I hexynyljphenyl]1-2-propenoic acid methyl ester, hydrogenation following the procedure of Example 5 gave the title compour-l (1.23 g; 90.8%) as a colorless oil.
Anal. Calcd for C26H4207S: C, 62.62: H, 8.49; S, 6.43.
Found: C, 62.27; HI, 8.75;9 S, 6.41.
Examo1e 12 Preparation of 2-(16-Hydroxyhexyl)-6-[4-(methylsulfonyl)butoxylbenzenepropanoic acid methyl ester.
Starting with 1.18 g (2.37 mmol) of rac-2'-[4-(methylsulfonyl)bvtoxy] [6-[(tetrahydro-2H-pyran-2-y1)oxylhexyl] benzenepropanoic acid methyl ester, hydrolysis following the procedure of Example 6 gave the title compound (0.79 g; 80.6%) as a colorless oil.
Anal. Calcd for (,22H3406S: C, 60.83; H, 8.27; S, 7.73.
Found: C, 61.02; H, 8.16; S, 7.45, WO 95/28386 PCT/EP11195/01262 Example 13 Prepa4ation of 2-(6-Bromohexyl)-6-[4-(methylsulfonyl)butoxy] benzenepropanoic acid methyl ester.
Starting with 0.72 g (1.73 mmol) of 2-(6-hydroxyhexyl)- 6- [4-(methylsulfonyl)butoxy] benzenepropanoic acid methyl ester, the title compound (0.71 g; 86.1%) was obtained as a colorless oil, following the procedure of Example 7.
Anal. Calcd for C2lH33BrO5S: C, 52.83; H, 6.97; Br, 16.74; S, 6.72. Found: C, 53.03; H, 6.90; Br, 16.49; S, 6.56.
Exampe 14 Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-[ 4 (methylsulfonyl)butoxy]benzenepropanoic acid methyl ester.
Starting with 0.34 g (1.39 mmol) of 4,6-diphenyl-2pyridone and 0.66 g (1.39 mmol) of 2-(6-bromohexyl)-6-[4- (methylsulfonyl)butoxy]benzenepropanoic acid methyl ester, the title compound (0.86 g; 96.2%) was obtained as a colorless oil, following the procedure of Example 8.
Example Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-[4- (methylsulfonyl)butoxy]benzenepropanoic acid.
Starting with 0.77 g (1.20 mmol) of 2-[6-[(4,6-diphenyl-2pyridinyl)oxy]hexyl] -6-[4-(methylsulfonyl)butoxy]benzenepropanoic acid methyl ester, hydrolysis following the procedure of Example 9 gave the title compound (0.49 g; 64.5%) as a white solid, mp 72.5-74.5 OC (recrystallized from hexane-ethyl acetate), WO 95/28386 PCII/B1195/01262 41 Anal, Calcd for C37H43N06S: C, 70.56; 6.88; N, 2.22; S, 5.09. Found: C, 70.26; H, 6.84; N, 2.05; S, 5.10.
Example 16 Preparation of rac-2-Hydroxy-6-[6-[(tetrahydro-2H-pyran-2yl)oxyl hexyi] ben zen epropanoic acid methyl ester.
Starting with 3.29 g (9.19 mmol) of rac-(E)-3-[2-hydroxy- 6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-l-hexynyllphenyl]-2propenoic acid methyl ester, hydrogenation following the procedure of Example 5 gave the title compound (3.07 g; 91.6%) a3 a colorless oil.
Anal. Calcd for C21H3205: C, 69.20; H, 8.85. Found: C, 69.26; H, 8.87.
Example 17 Preparation of 2-Hydroxy-6-(6-hydroxyhexyl)benzenepropanoic acid methyl ester.
Starting with 3.02 g (8.29 mmol) of rac-2-hydroxy-6-[6- [(tetrahydro-2H-pyran -2-yl) oxy] hexyl] ben zenepropan oic acid methyl ester, hydrolysis following the procedure of Example 6 gave the title compound (2.13 g; 91.7%) as a colorless oil.
Anal. Calcd for C16H2404: C, 68.55; H, 8.63. Found: C, 68.19; H, 8.18.
Example 18 Preparation of 3-Hydroxy-2-(3-hydroxy-3-methylbutyl)benzenehexanol.
To a stirred solution of 2.0 g (7.13 mmol) of 2-hydroxy-6- (6-hydroxyhexyl)benzenepropanoic acid methyl ester in 40 mL WO 95/28386 ITTIC, 1195/01262 42 of THF was added 20 mL of methylmagnesium chloride solution in THF (3M; 60 mmol), at room temperature, and the resulting solution was then refluxed for 4.33 hr. After being cooled to room temperature, the reaction mixture was treated with 75 mL of 1N aqueous sulfuric acid and the mixture was worked-up with ethyl acetate in the usual manner. The crude product was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate to afford 1.81 g of the title compound as a white solid, mp 72-73.5 oC.
Anal. Calcd for C17H2803: C, 72.82; H, 10.07. Found: C, 72.79; H, 10.30.
Example 19 Preparation of 4-[3-(6-Hydroxyhexyl)-2-(3-hydroxy-3methylbutyl)phenoxy]butanoic acid ethyl ester.
A mixture of 0.68 g (2.41 mmol) of 3-hydroxy-2-(3hydroxy-3-methylbutyl)benzenehexanol, 0.47 g (2.42 mmol) of ethyl 4-bromobutyrate and 1.33 g (9.66 mmol) of anhydrous, granular potassium carbonate in 25 mL of 2-butanone was stirred and refluxed for 21.5 hr. A second portion of ethyl 4bromobutyrate (0.24 g; 1.25 mmol) in 5 mL of 2-butanone was added and the reaction mixture was stirred and refluxed for an additional 22 hr. After being cooled to room temperature, the mixture was filtered through some anhydrous magnesium sulfate, and the solids were washed thoroughly with ethyl acetate. The filtrate and the washings were combined and concentrated. A second run was carried out starting with 0.91 g (3.24 mmol) of 3-hydroxy-2-(3-hydroxy-3-methylbutyl)benzenehexanol. The crude products from both runs were combined and purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate to afford 2.09 g (93.7%) of the title compound as a colorless oil.
WO 95/28380 43 Anal. Calcd for C23H3805: C, 70.02; H, 9.71. Found: C, 69.99; H, 9.57.
Example Preparation of 4- [3-(6-Bromohexyl)-2-(3-.hydroxy-3 methylbutyl)phenoxy]butanoic acid ethyl ester.
Starting with 2.04 g (5.16 mmol) of 4-[3-(6-hydroxyhexyl)-2-(3-hydroxy-3-methylbutyl)phenoxy] butanoic acid ethyl ester, the title compound (2.11 g; 89.4%) was obtained as a colorless oil, following the procedure of Example 7.
Anal. Calcd for C23H37BrO4: C, 60.39; H, 8.15; Br, 17.47.
Found: C, 60.36; H, 8.06; Br, 17.66.
Example 21 Preparation of 4- [6-[(4,6-Diphenyl-2-pyridinyl)oxylhexyll-2- (3 -hydro xy -3 -methylbu tyl)phen oxy] bu tan oic acid ethyl ester.
Starting with a mixture of 0.59 g (2.39 minol) of 4,6diphenyl-2-pyridone and 1.09 g (2.39 mmol) of bromohexyl)-2-(3-hydroxy-3 -methylbutyl)phenoxy] butanoic acid ethyl ester, the title compound (1.43 g; 95.8%) was obtained as a colorless oil, following the procedure of Example 8.
Anal. Calcd for C40H4qN05: C, 77.01; H, 7.92; N, 2.25.
Found: C, 76.54; H, 7.77; N, 2.15.
Example 22 Preparation of 4- [6-[(4,6-Diphenyl.-2-pyridinyl)oxylhexyl] -2- (3-hydroxy-3-methylbutyl)phenoxylbutanoic acid.
Starting with 1.36 g (2.18 mmol) of dip heny I-2-pyridinyl) oxyl hex yl 2 -hydroxy-3 -methylb utyl) WO 95/28386 PCTIEP95/01262 44 phenoxy]butanoic acid ethyl ester and following the procedure of Example 9, the title compound (1.08 g; 83.6%) was obtained as a white solid, mp 97.5-98.5 OC (recrystallized from hexaneethyl acetate).
Anal. Calcd for C38H45NO5: C, 76.61; H, 7.61; N, 2.35.
Found: C, 76.30; H, 7.88; N, 2.26.
Example 23 Preparation of 4-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-3-(3ethoxy-3-oxopropyl)benzenpentanoic acid ethyl ester.
Starting with a mixture of 0.24 g (0.97 mmol) of 4,6diphenyl-2-pyridone and 0.46 g (0.97 mmol) of 4-(6bromohexyl)-3-(3-ethoxy-3-oxopropyl)benzenepentanoic acid ethyl ester, the title compound (0.56 g; 90.3%) was obtained as a colorless oil, following the procedure of Example 8.
Anal. Calcd for C41H49NO5: C, 77.45; H, 7.77; N, 2.20.
Found: C, 77.22; H, 7.52; N, 2.11.
Example 24 Preparation of 3-(2-Carboxyethyl)-4-[6-[(4,6-diphenyl-2pyridinyl)oxy]hexyl]benzenepentanoic Acid.
Starting with 0.49 g (0.77 mmol) of 4-[6-[(4,6-diphenyl-2pyridinyl)oxy]hexyl]-3-(3-ethoxy-3-oxopropyl)benzenepentanoic acid ethyl ester and following the procedure of Example 9, the title compound (0.37 g; 82.9%) was obtained as a white solid, mp 104.5-106.5 0 C (recrystallized from hexane-ethyl acetate).
1.
WO 95/28386 :PCTIEP95/01262 45 Example Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-5-(4methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester.
A mixture of 0.68 g (2.75 mmol) of 4,6-diphenyl-2pyridone, 1.145 g (2.50 mmol) of 2-[6-[(methylsulfonyl)oxy]hexyl]-5-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester, 0.76 g (5.5 mmol) of anhydrous potassium carbonate, 0.037 g (0.25 mmol) of sodium iodide, and 6.2 mL of N,N-dimethylformamide was stirred and heated at 85-90 oC. for 16 hr. The reaction mixture was cooled and filtered with suction. The solids were washed with ethyl acetate and then the filtrate and washes were combined and concentrated in vacuo. The oily residue was flash-chromatographed on silica gel, eluting with hexane-ether mixtures. There was obtained 0.56 g of the title diester as a pale-yellow oil.
Example 26 Preparation of 5-(3-Carboxypropoxy)-2-[6-[(4,6-diphenyl-2pyridinyl)oxy]hexyl]benzenepropanoic acid.
A mixture of 0.56 g (0.92 mmol) of 2-[6-[(4,6-diphenyl- 2-pyridinyl)oxy]hexyl] -5-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester from the preceding example, 0.26 g (4.64 mmol) of potassium hydroxide, and 15 mL of methanol was stirred and refluxed for 20 hr. The resulting solution was cooled and concentrated in vacuo. The residue was dissolved in water and the aqueous, alkaline solution was extracted once with ether (the extract was discarded) before being acidified with 3N HC1. The mixture was worked-up with dichloromethane in the usual manner giving a solid product. Recrystallization from acetonitrile gave the title diacid (0.4 g; 75%) as a colorless solid, mp 133-134 oC.
WO 95/28386 PCIMIP95/01262 46 Anal. Calcd for C36H39N06: C, 74.33; H, 6.76; N, 2.41.
Found: C, 73.92; H, 6.60; N, 2.34.
EXAMPLE 27 Preparation of 2-[6-[[6-(4-Fluorophenyl)-4-phenyl-2-pyridinyl]oxy]hexyl] -6-(4-methoxy-4-oxobutoxy) benzenepropanoic Acid Methyl Ester.
Using the procedure of Example 2, 4-phenyl-6-(4-fluorophenyl)-2-pyridone was alkylated with 2-(6-iodohexyl)-6-(4methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester giving the title diester in quantitative yield, as a pale-yellow oil.
EXAMPLE 28 Preparation of 2-(3 -Carboxypropoxy)-6- [[6-(4-fluoro-phenyl)-4phenyl-2-pyridinyl)oxy]hexyllbenzenepropanoic Acid.
Using the procedure of Example 3, flu orophenyl) -4-ph enyl -2-pyridinyl] oxy h exyl] 6-(4-m eth oxy-4oxobutoxy)benzene-propanoic acid methyl ester from the preceding Example w~as saponified giving the title diacid monohydrate, in 29% yield, as a colorless solid, mp 78.5-81.0 OC., recrystallized from acetonitrile.
Anal. Calcd for C 36
H
38 FN0 6
*H
2 0: C, 70.00; H, 6.53; N, 2.27.
Found: C, 70.25; H, 6.27; N, 2.24.
WO 95/28386 I)CIVE1195/01262 47 EXAMPLE 29 Preparation of 2-(4-Methoxy-4-oxobutoxy)-6-[6-[[4-phenyl-6- (2-thienyl)-2-pyridinyl]oxy]hexyl]benzene-propanoic Acid Methyl Ester.
Using the procedure of Example 2, 4-phenyl-6-(2-thienyl)- 2-pyridone was alkylated with 2-(6-iodohexyl)-6-(4-methoxy-4oxobutoxy)benzenepropanoic acid methyl ester giving the title diester in 94% yield, as a pale-yellow oil.
EXAMPLE Preparation of 2-(3-Carboxypropoxy)-6-[6-[[4-phenyl-6-(2thienyl)-2-pyridinyl]oxy] hexyl] benzenepropanoic Acid.
Using the procedure of Example 3, 2-(4-methoxy-4-oxobutoxy)-6-[6-[[4-phenyl-6-(2-thienyl)-2-pyridinyl]oxy]hexyl] benzenepropanoic acid methyl ester from the preceding Example was saponified giving the title diacid, in 33% yield, as a colorless solid, mp 119.0-120.5 oC., recrystallized from acetonitrile.
Anal. Calcd for C 34
H
37 N0 6 S: C, 69.48; H, 6.35; N, 2.38.
Found: C, 69.43; H, 6.47; N, 2.29.
EXAMPLE 31 Preparation of 2-(6-Hydroxyhexyl)-6-[[4-(methoxy-carbonyl)phenyl]methoxy]benzenepropanoic Acid Methyl Ester.
A mixture of 1.15 g (3.16 mmol) of rac-2-hydroxy-6-[6- [(tetrahydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester from Example 16, 1.59 g (6.94 mmol) of 4bromomethylbenzoic acid methyl ester and 2.62 g (18.93 mmol) of anhydrous, granular potassium carbonate in 30 mL of 2butanone was heated at reflux in an oil bath for 20.5 hr. The
I
WO 95/28386 PCT/GEP95/01262 48 mixture was cooled to room temperature and filtered through anhydrous magnesium sulfate. The filter cake was washed with ethyl acetate and then the filtrate and washes were combined and concentrate in vacuo. The residue was dissolved in 50 mL of methanol, concentrated sulfuric acid (1 mL) was added, and the resulting solution was stirred at room temperature for 21 hr.
Most of the methanol was removed in vacuo and the residue was taken up in 250 mL of ethyl acetate. The solution was washed with saturated sodium bicarbonate solution and work-up was completed in the usual manner. Flash chromatography of the residue on 200 g of silica gel (eluting with 2:1 hexane-ethyl acetate) afforded 1.01 g of the title compound as a white solid, mp 60 oC.
Anal. Calcd for C 2 5
H
32 0 6 C, 70.07; H, 7.53. Found: C, 69.97; H, 7.59.
EXAMPLE 32 Preparation of 2-(6-Bromohexyl)-6-[[4-(methoxy-carbonyl)phenyl]methoxy]benzenepropanoic Acid Methyl Ester.
To a mixture of 0.50 g (1.17 mmol) of 2-(6-hydroxyhexyl)- 6-[[4-(methoxycarbonyl)phenyl]methoxy]benzenepropanoic acid methyl ester, 1.17 g (3.51 mmol) of carbon tetrabromide and 0.92 g (3.51 mmol) of triphenylphosphine was added 25 mL of ether and the resulting mixture was stirred at room temperature for 24.5 hr. The mixture was filtered through celite, and the filter cake was washed thoroughly with ether. The filtrate and washes were combined and concentrated in vacuo. Flash chromatography of the residue on 70 g of silica gel (eluting with 8:1 hexane-ethyl acetate) afforded 0.32 g of the title compound as a colorless oil.
Anal. Calcd for C 25
H
31 BrO 5 C, 61.10; H, 6.36; Br, 16.26.
Found: C, 61.03; H, 6.52; Br, 16.36.
I WO 95/28386 PC''/EPi95/01262 49 EXAMPLE 33 Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-[[4- (methoxycarbonyl)phenyl]methoxy]benzenepropanoic Acid Methyl Ester.
A mixture of 1.35 g of crude 2-(6-bromohexyl)-6-[[4- (methoxycarbonyl)phenyl]methoxy]benzenepropanoic acid meiyl ester, 0.68 g (2.75 mmol) of 4,6-diphenyl-2-pyridone, and 0.76 g (2.75 mmol) of silver carbonate, in 50 mL of toluene was stirred and refluxed, protected from light, for 45.8 hr. The mixture was cooled to room temperature and filtered through anhydrous magnesium sulfate. The filter cake was washed thoroughly with ethyl acetate and then the filtrate and washes were combined and concentrated in vacuo. Flash chromatography of the residue on 300 g of silica gel (eluting with 7:1 hexane-ethyl acetate) afforded 1.06 g (71.3% for two steps) of the title compound as a pale yellow oil.
Anal. Calcd for C 42
H
43 N0 6 C, 76.69; H, 6.59; N, 2.13. Found: C, 76.46; H, 6.56; N, 2.09.
EXAMPLE 34 Preparation of 2-[(4-Carboxyphenyl)methoxy]-6-[6-[(4,6diphenyl-2-pyridinyl)oxy]hexyl]benzenepropanoic Acid.
To a mixture of 863.2 mg (1.31 mmol) of dip henyl-2-pyridinyl)oxy] hexyl] [[4-(methoxyc arbonyl)phenyl]methoxy] benzenepropanoic acid methyl ester in 8 mL of tetrahydrofuran and 8 mL of water was added 187.8 mg (4.48 mmol) of lithium hydroxide monohydrate and the reaction mixture was stirred at room temperature for 113 hr. After the addition of 15 mL of 3N aqueous sulfuric acid, the mixture was extracted twice with ethyl acetate. The organic solutions were combined and washed with 50 mL of 3N aqueous sulfuric acid I ru WO 95/28386 PC'1'11T/EP195/01262 50 and work-up was completed in the usual manner. The crude product was recrystallized from hexane-ethyl acetate to give 688 mg of the title compound as an off-white solid, mp 100- 103 oC.
Anal. Calcd for C 40
H
39
NO
6 C, 76.29; H, 6.24; N, 2.22. Found: C, 75.98; H, 6.24; N, 2.16.
EXAMPLE Preparation of 2-(6-Hydroxyhexyl)-6-[[2(methoxycarbonyl) phenyl]methoxy]benzenepropanoic Acid Methyl Ester.
Starting with 810 mg (2.22 mmol) of 2-hydroxy-6-[6- [(tetrahydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester and 1.12 g (4.89 mmol) of 2-bromomethylbenzoic acid methyl ester, the title compound (635 mg; 66.8%) was obtained as a tan solid, mp 43-44 oC., following the procedure of Example 31.
Anal. Calcd for C 25
H
32 0 6 C, 70.07; H, 7.53. Found: C, 70.00; H, 7.62.
EXAMPLE 36 Preparation of 2-(6-Bromohexyl)-6-[[2-(methoxycarbonyl)phenyl]methoxy]benzenepropanoic Acid Methyl Ester.
Starting with 470 mg (1.10 mmol) of 2-(6-hydroxyhexyl)- 6-[[2-(methoxycarbonyl)phenyl]methoxy]benzenpropanoic acid methyl ester, the title compound (518 mg; 96.1%) was obtained as a colorless oil, following the procedure of Example 32.
Anal. Calcd for C 25
H
31 BrO 5 C, 61.10; H, 6.36; Br, 16.26.
Found: C, 61.09; H, 6.43; Br, 16.21.
c~ RI~C WO 95/20386~ ITIC/1111119.5/012( 2 51 EXAMPLE 37 Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxyhexyl]-6-[[2- (methoxycarbonyl)phenyl]methoxy]benzenepropanoic Acid Methyl Ester.
A mixture of 1.04 g of crude 2-(6-bromohexyl)-6-[[2- (methoxycarbonyl phenyl]methoxy] benzenepropanoic acid methyl ester, 0.53 g (2.12 mmol) of 4,6-diphenyl-2-pyridone, 1 0 and 0.59 g (2.12 mmol) of silver carbonate in 50 mL of toluene was stirred and refluxed, protected from light, for 67 hr. Workup as described in Example 33 gave a residue which was purified by flash chromatography on 300 g of silica gel (eluting with 6:1 hexane-ethyl acetate). This afforded 0.78 g (80.4% for 2 steps) of 1 5 the title compound as a yellow oil.
Anal. Calcd for C 4 2
H
4 3 N0 6 C, 76.69; H, 6.59; N, 2.13. Found: C, 76.53; H, 6.60; N, 2.17.
EXAMPLE 38 Preparation of 2-[(2-Carboxyphenyl)methoxy]-6-[6.-[(4,6diphenyl-2-pyridinyl)oxy]hexyl]benzenepropanoic Acid.
Starting with 732 mg (1.11 mmol) of 2-[6-[(4,6-diphenyl-2pyridinyl)oxy]hexyl]-6-[[2-(methoxycarbonyl)phenyl]methoxy]benzenepropanoic acid methyl ester and following the saponification procedure of Example 34, the title compound was obtained as a white solid, mp 134.5-137.5 oC. (recrystallized from hexane-ethyl acetate).
Anal. Calcd for C 40
H
3 9 N0 6 C, 76.29; H, 6.24; N, 2.22. Found: C, 75.91; H, 6.09; N, 2.14.
11 9 WO 95/28386 11CII/E1195/0% )2 -52 EXAMPLE 39 Preparation of 2-(6-Hiydroxyhexyl)-6-fl3(methoxy-carbonyl)phenyllmethoxylbenzenpropaloic Acid Methyl Ester.
Starting with 1.35 g (3.69 mmol) of 2-hydroxy-6-46- [(tetrahydro-2H-pyran-2-yl)oxy] hexyl] benzenepropanoic acid methyl ester and 1.86 g (8.13 mmol) of 3-bromomethylbenzoic acid methyl ester, the title compound (1.11 g; 70.1%) was obtained as a colorless oil, following the procedure of Example 31.
Anal. Calcd for C 25
H
32 0 6 C, 70.07; H, 7.53. Found: C, 69.91; H, 7.61.
EXAMPLE Preparation of 2-(6-Bromohexyl)-6-[ [3-(methoxycarbonyl)phenyl] methoxy] benzenepropanoic Acid Methyl Ester.
Starting with 1.11 g (2.59 mmol) of 2-(6-hydroxyhexyl)-6- [[3-(methoxycarbonyl)phenyllmethoxy]benzelpropaloic acid methyl ester, the title compound (0.96 g; was obtained as a colorless oil, following the procedure of Example 32.
Anal. Calcd for C 25
H
3 ,BrO 5 C, 61.10; H, 6.36; Br, 16.26.
Found: C, 61.08; H, 6.29; Br, 16.34.
EXAMPLE 41 Preparation of 2- [6-[(4,6-Diphenyl-2-pyridinyl)oxy] hexylll-6- 3- (meth oxycarb onyl)phenyll meth oxyl ben zenepropan oic Acid Methyl Ester.
A mixture of 919 mg (1.87 mmol) of 2-(6-bromohexyl)-6- [[I3-(methoxycarbonyl)phenyllmethoxylbenzenepropanoic acid methyl ester, 462 mg (1.87 mmol) of 4,6-diphenyl-2-pyridone and 515 mg (1.87 mmol) of silver carbonate in 50 niL of toluene WO 95/28386 PICT/ElIP95/01262 53 was stirred and refluxed for 44.7 hr. A second portion of 4,6diphenyl-2-pyridone (100.2 mg; 0.41 mmol) was added and the reaction was iontinued for another 7 hr, and then cooled to room temperature while stirring for 3 d. Work-up as described in Example 33 gave a residue which was purified by flash chromatography on 300 g of silica gel (eluting with 6:1 hexaneethyl acetate). This afforded 1.09 g of the title compound as a pale yellow oil.
Anal. Calcd for C 42
H
43
NO
6 C, 76.69; H, 6.59; N, 2.13. Found: C, 76.58; H, 6.47; N, 2.05.
EXAMPLE 42 Preparation of 2-[(3-Carboxyphenyl)methoxy]-6-[6-[(4,6diphenyl-2-pyridiny!)oxy]hexyl]benzenepropanoic Acid.
Starting with 1.01 g (1.54 mmol) of 2-[6-[(4,6-diphenyl-2pyridinyl)oxy]hexyl]-6-[[3-(methoxycarbonyl)phenyl]methoxy]benzenepropanoic acid methyl ester and following the procedure of Example 34, the title compound was obtained as an off-white solid, mp 157.5-159.5 oC. (recrystallized from hexane-ethyl acetate).
EXAMPLE 43 Preparation of '.-[(2-Oxo-2H-l-benzopyran-5-yl)oxy]- butanoic Acid Ethyl Ester.
A mixture of 8.78 g (54.15 mmol) of 10.56 g of ethyl 4-bromobutyrate, 18.93 g (137 rmiol) of anLydrous, granular potassium carbonate, and 50 mL of dry dimethyl suifoxide was stirred at room temperature for 3 d. The resulting slurry was filtered with suction over a Celite pad and then the filter cake was washed with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo. The I iple~uraP* P aPn~a~8plY-PI--~ l~nnn~~~ WO 95/28386 PCIVE. P9/01262 54 residue was dissolved in ethyl acetate and the solution was washed 3 times with water. Work-up was completed in the usual manner giving an oil which was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate mixtures. There was obtained 9.90 g of the title ester as a pale-yellow oil.
EXAMPLE 44 Preparation of (E)-4-[3-Hydroxy-2-(3-methoxy-3-oxo-lpropenyl)phenoxy)butanoic Acid Methyl Ester.
A solution of 9.90 g (35.87 mmol) of 4-[(2-oxo-2H-1acid ethyl ester from the preceding Example, 20 mL of 25% methanolic sodium methoxide, and 60 mL of methanol was stirred and refluxed for 32 fir and then kept at room temperature for 24 hr. The resulting yellow solution was concentrated in vacuo giving a solid residue which was treated with ethyl acetate and excess 1N aqueous hydrochloric acid. The mixture was worked-up with ethyl acetate and ether in the usual manner (the organic extracts were additionally washed with saturated, aqueous sodium bicarbonate solution) giving 9.42 g of a white solid. This material was dissolved in 50 mL of methanol and 0.934 g of p-toluenesulfonic acid monohydrate was added. The solution was stirred and refluxed for 24 hr and then cooled and concentrated in vacuo.
The residue was worked-up with ethyl acetate in the usual manner (the organic extracts were additionally washed with saturated, aqueous sodium bicarbonate solution) giving 11.07 g of a beige solid. This material was purified by flash chromatography on 1500 g of silica gel, eluting with hexane-ethyl acetate mixtures. There was obtained 2.60 g of the pure title diester as a colorless solid.
~-P3 WO 95/28386 PCI' P95/012621i 55 EXAMPLE Preparation of (E)-4-[3-[(5-Bromopentyl)oxy)]-2-(3-methoxy-3oxo-l-propenyl)phenoxy]butanoic Acid Methyl Ester.
A mixture of 2.60 g (8.84 mmol) of (E)-4-[3-hydroxy-2-(3methoxy-3-oxo-l-propenyl)phenoxy]butanoic acid methyl ester from the preceding Example, 9.73 mL (16.27 g; 70.75 mmol) of 3.86 g (27.99 mmol) of anhydrous, granular potassium carbonate, and 150 mL of acetonitrile was stirred at room temperature, for 48 hr. The resulting slurry was diluted with ether and filtered with suction over a pad of Celite. The filter cake was washed with ether and then the filtrate and washes were combined and concentrated in vacuo. The oily residue was flash chromatographed on 750 g of silica gel, eluting with hexane-ethyl acetate mixtures. There was obtained 3.20 g of the title bromide as a pale-yellow oil.
EXAMPLE 46 Preparation of (E)-4-[3-[[5-[(4,6-Diphenyl-2-pyridinyl)oxy] pentyl]oxy)]-2-(3-methoxy-3-oxo- 1 -propenyl)phenoxy] butanoic Acid Methyl Ester.
Alkylation of 4,6-diphenyl-2-pyridone (1.23 g; 5 mmol) with (E)-4-[3-[(5-bromopentyl)oxy)]-2-(3-methoxy-3-oxo-1propenyl)- phenoxy]butanoic acid methyl ester (2.22 g; 5 mmol) from the preceding Example, was carried out using the procedure of Example 2. There was obtained 2.19 g of the title compound as an oil.
WO 95/28386 PCTIEP95/01262 56 EXAMPLE 47 Preparation of 2-[[5-[(4,6-Diphenyl-2-pyridinyl)oxy]- pentyl]oxy]-6-(4-methoxy-4-oxobutoxy)benzenepropanoic Acid Methyl Ester.
A mixture of 2.19 g (3.59 mmol) of diphenyl-2-pyridinyl)oxy]pentyl]oxy)] -2-(3-methoxy-3-oxo- 1propenyl)- phenoxy]butanoic acid methyl ester from the preceding Example, 0.219 g of 10% palladium on carbon, 25 mL of methanol, and 25 mL of ethyl acetate was stirred in an atmosphere of hydrogen, at room temperature, until gas uptake ceased. The mixture was filtered with suction over a pad of Celite and then the filter cake was washed with ethyl acetate.
The filtrate and washes were combined and concentrated in vacuo. There was obtained 1.86 g of the title diester as a pale-yellow oil.
EXAMPLE 48 Preparation of 2-(3-Carboxypropoxy)-6-[[5-[(4,6-diphenyl-2pyridinyl)oxy]pentyl]oxy]benzenepropanoic Acid.
Using the procedure of Example 3, 2-[[5-[(4,6-diphenyl-2pyridinyl)oxy]pentyl]oxy]-6-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester from the preceding Example was saponified giving the title diacid, in 46.9% yield, as a colorless solid, mp 130-131 oC., recrystallized from acetonitrile.
Anal. Calcd for C 3 5
H
37
NO
7 C, 72.02; H, 6.39; N, 2.40. Found: C, 71.86; H, 6.35; N, 2.39.
II P I WO 95/28386 PCT/EP95/01262 57 EXAMPLE 49 Preparation of rac-(E.)-3-[3-[2-(3-Methoxy-3-oxo-1-propenyl)-3- [6-[(tetrahydro-2H-pyran-2-yl)oxy] -1-hexynyl]phenoxy]propyl]benzoic Acid Ethyl Ester.
A mixture of 1.45 g (4.04 mmol) of rac-(E)-3-[2-hydroxy-6- [6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2propenoic acid methyl ester, 0.841 g (4.04 mmol) of 3-(3hydroxypropyl)- benzoic acid ethyl ester, 3.15 g (12.0 mmol) of triphenylphosphine, 1.91 mL (12 mmol) of diethyl azodicarboxylate, and 100 mL of dry tetrahydrofuran was stirred at room temperature for 3 d. Additional triphenylphosphine (3.15 g) and diethyl azodicarboxylate (1.91 mL) were added and stirring was continued for 24 hr. The reaction mixture was concentrated in vacuo and then the oily residue was flash chromatographed on 500 g of silica gel. Elution with hexane-ethyl acetate mixtures afforded 1.70 g of the title compound as a slightly pink oil.
EXAMPLE Preparation of rac-2-[3-[3-(Ethoxycarbonyl)phenyl]- propoxy]-6- [6-[(tetrahydro-2H-pyran-2-yl)oxy]- hexyl]benzenepropanoic Acid Methyl Ester.
A mixture of 1.70 g (3.10 mmol) of methoxy-3-oxo- 1 -propenyl)-3-[6- [(tetrahydro-2H-pyran-2yl)oxy]-l-hexynyl]phenoxy]propyl]benzoic acid ethyl ester from the preceding Example, 0.5 g of 10% palladium on carbon, and 170 mL of methanol was stirred in an atmosphere of hydrogen, at room temperature, until gas uptake ceased. The catalyst was removed by suction filtration over Celite and then the filtrate was concentrated in vacuo. There was obtained 1.53 g of the title compound as an oil.
WO 95/28386 PCT/EP95/01262 58 EXAMPLE Preparation of 2-[3-[3-(Methoxycarbonyl)phenyl]propoxy]-6-(6hydroxyhexyl)benzenepropanoic Acid Methyl Ester.
A solution of 1.53 g (2.76 mmol) of rac-2-[3-[3-(ethoxycarbonyl)phenyl]propoxy]-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester from the preceding Example, 0.1 g of p-toluenesulfonic acid monohydrate, and 50 mL of methanol was stirred and refluxed for 20 hr before being cooled and concentrated in vacuo. The residue was worked-up with ether in the usual manner giving an oily residue, 1H NMR analysis of which revealed complete removal of the tetrahydropyranyl protecting group but the presence of a mixture of methyl and ethyl esters. This material was retreated with methanol-p-toluenesulfonic acid monohydrate (24 hr reflux; 48 hr room temperature) affording 1.30 g (100%) of a yellow oil which was now mainly the desired, title dimethyl ester.
EXAMPLE 52 Preparation of 2-[3-[3-(Methoxycarbonyl)phenyl]propoxy]-6-[6- [(methylsulfonyl)oxy]hexyl]benzenepropanoic Acid Methyl Ester.
To a stirred solution of 1.30 g (ca. 2.76 mmol) of (methoxycarbonyl)phenyl]propoxy]-6-(6-hydroxyhexyl)benzenepropanoic acid methyl ester from the preceding Example, 2.9 mL of triethylamine, and 20 mL of ethyl acetate was added 0.9 mL (11.63 mmol) of methanesulfonyl chloride, with ice-bath cooling.
The resulting slurry was stirred at 0-5 oC. for 3.5 hr and then refrigerated for 24 hr. The reaction mixture was treated with 1N hydrochloric acid and ice, and then worked-up with ether in the usual manner. This afforded 1.59 g (100%) of the title mesylate as a pale-yellow oil.
WO 95/28386 PCT/EP95/01262 59 EXAMPLE 53 Preparation of 2-(6-Iodohexyl)-6-[3-[3-(methoxycarbonyl) phenyl]propoxy]benzenepropanoic Acid Methyl Ester.
Using the procedure of Example 1, 2-[3-[3-(methoxycarbonyl)phenyl]propoxy]-6-[6-[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester from the preceding Example was converted into the title iodide, an oil, in quantitative yield.
EXAMPLE 54 Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-[3- [3-(methoxycarbonyl)phen, l]propoxy]benzene-propanoic Acid Methyl Ester.
Using the procedure of Example 2, 0.828 g (3.35 mmol) of 4,6-diphenyl-2-pyridone was alkylated with 2-(6-iodohexyl)-6- [3-(methoxycarbonyl)phenyl]propoxy] benzenepropanoic acid methyl ester from the preceding Example. There was obtained 0.96 g of the title diester as a pale-yellow oil.
EXAMPLE Preparation of 2-[3-(3-Carboxyphenyl)propoxy]-6-[6-[(4,6diphenyl-2-pyridinyl)oxy]hexyl]benzenepropanoic Acid.
Using the procedure of Example 3, 2-[6-[(4,6-diphenyl-2pyridinyl)oxy]hexyl]-6-[3-[3-(methoxycarbonyl)phenyl] propoxy]benzenepropanoic acid methyl ester (0.96 g) from the preceding Example was saponified. There was obtained 0.58 g of the title diacid as a colorless solid, mp 102-105 oC., recrystallized from acetonitrile.
1 WO 95/28386 PCTIE P95/01262 60 Anal. Calod for C 42
H
43 N0 6 C, 76.69; H, 6.59; N, 2.13. Found: C, 76.39; H, 6.63; N, 2.12.
EXAMPLE 56 Preparation of rac-(I.)-2-[3-[2-(3-Methoxy-3-oxo-1 -propenyl)-3- [(tetrahydro-2H-pyran-2-yl)oxy]- 1-hexynyllphenoxy]propyl] benzoic Acid Methyl Ester.
Using the procedure of Example 49, 1.45 g (4.04 mmol) of rac-(E.)-3 -[2-hydroxy-6- [(tetrahydro-2H-pyran-2-yl)oxy]- 1hexynylllphenyl]-2-propenoic acid methyl ester and 0.784 g (4.04 mmol) of 2-(3-hydroxypropyl)benzoic acid methyl ester were converted into the title diester, a colorless oil, in quantitative yield.
EXAMPLE 57 Preparation of rac-2-[3-[2-(Methoxycarbonyl)phenyll- propoxy]- 6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]hexyl] benzenepropanoic Acid Methyl Ester.
Using the procedure of Example 50, rac-(jj)-2-[3-[2- 1 3methoxy -3 -oxo-l1-propenyl)-3 [(tetrahydro-2H-pyran-2yl)oxy] -1-hexynyllphenoxylpropyl]benzoic acid methyl est-.r from the preceding Example (2.2 g) was catalytically hydrogenated giving the title compound, a colorless oil, in 97% yield (2.11 g).
WO 95/28386 PCT/EP95/01262 61 EXAMPLE 58 Preparation of 2-[3-[2-(Methoxycarbonyl)phenyl]propoxy]-6-(6hydroxyhexyl)benzenepropanoic Acid Methyl Ester.
Using the procedure of Example 51 with the modification that only one methanol-p-toluenesulfonic acid treatment was.
employed, rac-2-[3-[2-(methoxycarbonyl)phenyl]propoxy]-6-[6- [(tetrahydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester (2.11 g) from the preceding Example, was converted into the title compound, a colorless oil, in 95% yield (1.69 g).
EXAMPLE 59 Preparation of 2-[3-[2-(Methoxycarbonyl)phenyl]propoxy]-6-[6- [(methylsulfonyl)oxy]hexyl]benzenepropanoic Acid Methyl Ester.
Using the procedure of Example 52, 2-[3-[2-(methoxycarbonyl)phenyl]propoxy]-6-(6-hydroxyhexyl) benzenepropanoic acid methyl ester from the preceding Example (1.69 g) was converted into the title mesylate, a yellow oil, in quantitative yield.
EXAMPLE Preparation of 2-(6-Iodohexyl)-6-[3-[2-(methoxycarbonyl)phenyl]propoxy]benzenepropanoic Acid Methyl Ester.
Using the procedure of Example 1, 2-[3-[2-(methoxycarbonyl) phenyl]propoxy]-6-[6-[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester, from the preceding Example, was converted into the title iodide, a pale-yellow oil, in quantitative yield.
WO 95/28386 .PC'I'/EP95/01202 -62 EXAMPLE 61 Preparation of [(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-[3 (meth oxyc arbonyl)ph enyll prop ox y] benzene-prop an oic Acid Methyl Ester.
Using the procedure of Example 2, 0.998 g (4.04 mmol) of 4,6-diphenyl-2-pyridone was alkylated with 2-(6-iodohexyl)-6- [3-[2-(methoxycarbonyl)phenyllpropoxylberlzenepropanoic acid methyl ester from the preceding Example. There was obtained 2.02 g of the title diester as a pale-yellow oil.
EXAMPLE 62 Preparation of 2-[3-(2--Carboxyphenyl)propoxy] diphenyl -2-pyridinyl)oxy] hexyl] ben zenepropan oic Acid.
Using the procedure of Example 3, 2-[6-[(4,6-diphenyl-2pyridinyl)oxy] hexyl] [2-(methoxycarbonyl)phenylllpropoxy] benzenepropanoic acid methyl ester (2.02 g) from the preceding Example was saponified. There was obtained 1.09 g of the title diacid as a colorless solid, mp 126-128 OC., recrystallized from acetonitrile.
Anal. Calcd for C 42
H
43 N0 6 C, 76.69; H, 6.59; N, 2.13. Found: C, 76.30; H, 6.75; N, 2.07.
WO 95/28386 PCT/P95/1262 63 EXAMPLE 63 TABLET FORMULATION (Wet Granulation) Ingredients mg/tablet 1. Compound 5.0 25.0 100.0 250.0 2. Lactose Anhydrous 108.4 88.4 89.0 222.5 3. Povidone K30 6.0 6.0 10.0 25.0 4. Magnesium Stearate 0.6 0.6 1.0 TOTAL 120.0 120.0 200.0 500.0 Compound A is 2-(3-Carboxypropoxy)-6-[6-[[4,6-diphenyl-2pyridinyl)oxy]hexyl]benzenepropanoic acid.
Manufacturing Procedure: 1) Mix Items 1 and 2 in a suitable mixer for 15 minutes.
2) Granulate the powder mix from Step 1 with 15% PVP solution.
3) Dry the granulation from Step 2 at 50 0
C.
4) Pass the granulation from Step 3 through a suitable milling equipment.
Add the Item 4 to the milled granulation from Step 4 and mix for 3 minutes.
6) Compress the granulation from Step 5 on a suitable press.
WO 95/28386 PCT/EP95/01262 Ingredients 1. Compound A 2. Lactose Hydrous 3. Corn Starch 4. Talc Magnesium Stearate
TO
64 EXAMPLE 64 CAPSULE FORMULATION mg/capsule 5.0 25 159 124 25 40 10.0 10.0 1.0 1.0 TAL 200.0 200.0 100 143 2 300.0 Manufacturing Procedure: 1) 2) 3) Mix Items 1, 2 and 3 in a suitable mixer for 30 minutes.
Add Items 4 and 5 and mix for 3 minutes.
Fill into suitable capsule.
I

Claims (15)

1. A compound of the formula (X)t(CR 5 R 6 ),Y R 1 N G(CH 2 )rt(O4 wher, in X is 0 or C=O; Y is CN, S(O)uR 8 NR 5 SO 2 R 8 OR 9 R" 0 or -64" Z is 5 R 6 X,-R' 0 -(O)y-(CR 5 R 6 X-OR 9 orR; R1, R' are, independently, aryl, substituted aryl, hietcroary!, lower alkyl or optionally substituted aralkyl; R' is hydrogen, lower alkyl, halogen or lower alkoxy; R' is hiydrcgen or lower alkyl; FR1, RI are, independently, each occurrence, hydrogen or lower atkyl; R' is hydroxy, lower alkoxy or NR 5 RI; R' is lower alkyl, aryl, substituted aryl or optionally substituted aralkyl; R' is hydrogen, lower alkyl., aryl, substituted aryl, optionally substituted aralkyl, lower 20 alkanoyl or aroyl; R" is COR', CONI-S0 2 R' or in is an integer from 3 to 8; ii anld s are, independently, an integer from I to 12; is an integer from 0 to 1; u is an integer from 0 to 2; v is an integer from 2 to 12; y is an integer 0; and z is an integer 0; with the proviso that either Y is R' 0 Or -C 6 1-1 4 R' 0 or Z is (CWWl.X-Rw or MO 0 and the further proviso that when n=1, Y is R' 0 or -C 6 H1 4 R' 0 WO 95/28386 PCT/EP95/01262 66 an optical isomer when R 5 and R 6 are not both hydrogen or the same lower alkyl and, when R 7 is hydroxy, a pharmaceutically acceptable salt thereof with a base.
2. A compound according to claim 1, wherein Y is R 1 0 or -C6H4R 10
3. A compound according to claim 1 or 2, wherein Z is -(0)y-(CR 5 R 6 )s-R 10 or R 1 0
4. A compound according to any one of claims 1-3, wherein R 1 and R 3 are aryl and R 2 and R 4 are hydrogen. A compound according to any one of claims 1-4, wherein Y is S(O)uR 8 OR 9 or R 10 and Z is-(O)y-(CR 5 R 6 )s-R 10 or -(O)y-(CR 5 R 6 )v-OR 9
6. A compound according to any one of claims wherein Y is R 10 Z is -(O)y-(CR 5 R 6 )v-OR 9 or -(O)y-(CR 5 R 6 )s- R 10 R 7 is hydroxy, R 9 is hydrogen, and R 10 is -COR 7
7. A compound according to claim 6, wherein X is 0, z is zero, t is 1, n is 3-5, y is zero and s or v is 2-6.
8. A compound according to any one of claims wherein Y is S(O)uR 8 or OR 9 Z is -(0)y-(CR 5 R 6 )s-R 10 R 7 is hydroxy, R 8 is lower alkyl, R 9 is hydrogen and R 10 is -COR 7
9. A compound according to claim 8, wherein X is O, z is zero, t is 1, n is 3-5, y is zero and s is 2-6. A compound according to claim 1, wherein the compound of formula I is selected from the group consisting of 2-(3-carboxypropoxy)-6-[6-[(4,6-diphenyl-2-pyridinyl)oxy]- hexyl]-benzenepropanoic acid; 2-[6-[(4,6-diphenyl-2-pyridinyl)- WO095128386 PCT/E 115/0 1202 67 oxy] hexyl]1 [(4-hydroxy-4-methylpentyl)-oxy] benzene- proparnoic acid; 2-[6-[4,6-diphenyl-2-pyridinyl)oxy]hexyl] (methylsulfonyl)butoxy]-benzenepropanoic acid; 4-[3-116-[(4,6- diphenyl-2-pyridinyl)oxylhexyl] -hydroxy-3 -methyl- butyl)phenoxy] butanoic acid; 3-(2-carboxyethyl)-4-[6-[(4,6- diph enyl -2 -pyridinyl) oxy Ih exyl benzen epen tan oic acid; and (3 -c~qrboxypropoxy)-2- 6-d-iphenyl-2-pyridinyl)oxy]hexyll benz_,i iepropanoic acid.
11. A compound according to claim 1, wherein the compound of formula I is selected from the group consisting of 2-[3 -(2-carboxyphenyl)propoxy] [(4,6-diphenyl-2- pyridin yl) oxy ]h exyllben zenepropan oic acid; 2-[3-(3-carboxy- phenyl)propoxy] [(4,6-diphenyl-2-pyridinyl)oxy] hexyli benzenepropanoic acid; 2-(3-carboxypropoxy)-6-[5-[(4,6- diphenyl -2-pyridinyl) oxyl pen tyl oxy b enzen eprop an oic acid; 2- (3 -carboxypropoxy)- 6- (4-phenyl -6 -flu oroph enyl)-2 pyridinyl)oxylhexyl]benzenepropanoic acid; 2-(3-carboxy- propoxy)-6- [(4-phenyl-6-(2-thienyl)-2-pyridinyl)oxyl- hexyllbenzenepropanoic acid; 2-[(4-carboxyphenyl)methoxy] -6- [(4,6-diphenyl-2-:pyridinyl)oxy]- hexyl] benzenepropanoic acid; 2-[(2-carboxyphenyl)methoxy]-6-[6-[(4,6-diphenyl-2- pyridinylNcx-y] hexyllbenzenepropanoic acid; and 2-[(3-carboxv- phenyl)methoxy] [(4,6-diphenyl-2-pyridinyl)oxy] hcxyllbenzenepropanoc acid.
12. A pharmaceutical composition especially for the treatment or prevention of inflammatory diseases such as psoriasis, rhinitis, chronic obstructive pulmonary di sese, inflammatory bowel disease, asthma, acute respiratory distress syndrome, cystic fibrosis, allergy, arthritis such as rheumatoid arthritis, dermatitis such as contact dermatitis, NSAID-induced gastropathy, gout, ischemia/perfusion injury and trau-ma- induced inflammation which contains an effective amount of a compound in accordance with any one of claims 1-11 or a ~lb~il~l~ %ll~uP~ lauor~l8 VO 95/28386 'PCT/lP95/01 262 68 pharinaceutically acceptable salt thereof with a base, and an inert carrier.
13. A process for the manufacture of compounds according to any one of claims 1-11, which process comprises a) reacting a compound of the general formula with a compound of the general -formula (X)t(CR 5 R 6 )jY (C H 2) (0)c 125 e 15 9c a o 0 o• oo 25 e *c 0 e o wherein L is a leaving group, R 1 R 2 R 3 R 4 R 5 R 6 X, m, n, z and t are as defined in claim 1 and Y' and Z' are Y and Z as defined in claim 1 with the proviso that in any COR 7 R 7 is lower alkoxy, b) saponifying a compound of the general formula I, wherein Y and/or Z contain(s) a -COR 7 group and R 7 is lower alkyl to mono- or di-acid derivatives, or c) reacting a compound of the general formula I, wherein the group(s) Y and/or Z contain(s) the group -COOH, with an amin of the formula PI' \VI'I)II 'SlA l.S'I!('l\6ll70-,1'* 2.1/91R -69- HNRR 1 3 wherein R 5 is as defined in claim 1 and R" 3 is hydrogen, lower alkyl or a group -SO 2 R and R 8 is as defined in claim 1, to the corresponding mono- or disubstituted amides or sulfonamides, or d) reacting a compound of the general formula I, wherein Y is -CN with a metal azide to give a compound of the formula I, wherein Y is 1H-tetrazol-5-yl, and e) if desired, converting a compound of the general formula I into a pharmaceutically acceptable salt.
14. Compounds in accordance with any one of claims 1-11 whenever prepared according to the process as claimed in claim 13 or by an obvious chemical equivalent thereof. A method for the treatment or prevention of inflammatory diseases from the group 20 which includes psoriasis, rhinitis, chronic obstructive pulmonary disease, inflammatory bowel disease, asthma, acute respiratory distress syndrome, cystic fibrosis, allergy, arthritis, dermatitis, NSAID-induced gastropathy, gout, ischemia/perfusion injury and trauma-induced inflammation which comprises administering to a subject in need of such treatment, a therapeutically or prophylactically effective amount of a compound according to any one of claims 1-1 optionally in combination with an inert carrier. 4 0 o .4 C .4 *4
16. The use of compounds according to any one of claims 1-11 in the control or prevention of inflammatory diseases, bowel disease, asthma, acute respiratory distress syndrome, cystic fibrosis, allergy, arthritis such as rheumatoid arthritis, dermatitis such as contact dermatitis, NSAID-induced T~ O /r o^V~ s I WI'Ii)O(.'Al.S\illI'l61OH87.P'69-21/f9 gastropathy, gout, ischemia/perfusion injury and trauma-induced inflammation, or for the manufacture of active pharmaceutical preparations.
17. Compounds of the formula according to any one of claims 1-11, methods for their manufacture or pharmaceutical compositions or methods of treatment involving/containing them, substantially as hereinbefore described with reference to the Examples. DATED this 21st day of January, 1998. F HOFFMANN-LA ROCHE AG By Its Patent Attorneys DAVIES COLLISON CAVE S *e S o CC o• C CS INTERNATIONAL SEARCH REPORT Inte nal Application No PCT/EP 95/01262 A. CIASSIFICAT'ION OF SUBJIiC IMA'IT"R IPC 6 C07D213/64 C07D409/04 A61K31/44 According to International Patent Classification (II'C or to both national classfication and IPC B. FlIElD)IS SiARCIIl) Minimum documentation searched (classification system followed by classification symbols) IPC 6 C07D A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data basc and, where practical, search terms used) C. DOCUMIENTS CONSIDIiRIH) TO Ifll il.liIVANT Category Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A WO-A-92 01675 (RHONE POULENC RORER SA) 6 1-17 February 1992 see page 1 page 2; claims 1,15-26 see page 35, line 28 line 29 see page 41, line 9 line see page 67, line 12 A WO-A-91 18880 (SMITHKLINE BEECHAM CORP) 12 1-17 December 1991 see the whole document F] Further documents are listed in the continuation of box C. Patent family members are listed in annex. SSpecial categories of cited documents: later document published after the international filing date or pronty date and not in conflict with the application but document defining the general state of the art which is not cted to understand the pnnciple or theory underlying the considerd to he of particular relevance invention earlier document hut published on or after the international document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw douhts on pnonty claim(s) or involve an inventive step when the document is taken alone which is cited to establish the puhlication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considerid to involve an inventive step when the document refernng to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled P document published pnrior to the International filing date hut in the art. later than the prnonty date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 17 July 1995
27. 07. Name and mailing address of the ISA Authonzed officer luropean Patent Office, P1.1. 5818 I'atcntlaan 2 NI. 2280 IIV Riiswijk Tel. 31-70) 340-2040, Tx. 31 651 epo nl, Bo ma P Fax: (i 31-70) 340-3016 B s Form PCT.ISA.210 (iecond sheet) (July 1992) I INTERNATIONAL SEARCH REPORT Informnation on patcnt family mcmberes Inte anal Applicallon No IPCT/EP 95/01262 Patent document I PbcaonPatent, faily Publication cited in search report dacjmember(s) date W0-A-9201675 06-02-92 FR-A- 2665159 31-01-92 AU-A- 8194891 18-02-92 CA-A- 2087848 25-01-92 EP-A- 0540604 12-05-93 US-A- 5366982 22-11-94 WO-A-9118880 12-12-SI AU-A- 7901791 31-12-91 CN-A- 1058016 22-01-92 EP-A- 0532550 24-03-93 HU-A- 64748 28-02-94 Farm PCTISA,210 (phtent (rnly annex) (July 1992)
AU22569/95A 1994-04-13 1995-04-06 Substituted pyridine leukotriene B4 antagonists Ceased AU690258B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US22824694A 1994-04-13 1994-04-13
US228246 1994-04-13
US39509295A 1995-03-06 1995-03-06
US395092 1995-03-06
PCT/EP1995/001262 WO1995028386A1 (en) 1994-04-13 1995-04-06 Substituted pyridine leukotriene b4 antagonists

Publications (2)

Publication Number Publication Date
AU2256995A AU2256995A (en) 1995-11-10
AU690258B2 true AU690258B2 (en) 1998-04-23

Family

ID=26922175

Family Applications (1)

Application Number Title Priority Date Filing Date
AU22569/95A Ceased AU690258B2 (en) 1994-04-13 1995-04-06 Substituted pyridine leukotriene B4 antagonists

Country Status (8)

Country Link
EP (1) EP0755381A1 (en)
JP (1) JP2866202B2 (en)
CN (1) CN1145619A (en)
AU (1) AU690258B2 (en)
BR (1) BR9507459A (en)
CA (1) CA2186252A1 (en)
NZ (1) NZ284069A (en)
WO (1) WO1995028386A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8093253B2 (en) * 2008-03-06 2012-01-10 Hoffmann-La Roche Inc. Leukotriene B4 inhibitors

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR930700445A (en) * 1990-06-07 1993-03-15 원본미기재 Benzoic acid derivatives for the treatment of leukotrienes-related diseases
FR2665159B1 (en) * 1990-07-24 1992-11-13 Rhone Poulenc Sante NEW PYRIDINE AND QUINOLEIN DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.

Also Published As

Publication number Publication date
CN1145619A (en) 1997-03-19
JP2866202B2 (en) 1999-03-08
NZ284069A (en) 1997-10-24
AU2256995A (en) 1995-11-10
JPH09505605A (en) 1997-06-03
WO1995028386A1 (en) 1995-10-26
EP0755381A1 (en) 1997-01-29
BR9507459A (en) 1997-11-11
CA2186252A1 (en) 1995-10-26

Similar Documents

Publication Publication Date Title
US4868216A (en) Sulfamoyl-substituted phenethylamine derivatives and process of producing them
US5130318A (en) Angiotensin ii antagonizers which are condensed pyridine derivatives
EP0580550B1 (en) Oxamic acid derivatives as hypocholesteremic agents
CA1301762C (en) Dichloroaniline derivatives
EP0129906B1 (en) Phenoxyalkoxy-3,4-dihydro-2h-1-benzopyran derivatives
HU205079B (en) Process for producing optionally alpha-substituted 4-(quinolin-2-ylmethoxy)-phenylacetic acids and their esters, as well as pharmaceutical compositions comprising such compounds
US4507498A (en) Phenoxycarboxylic acids
CA1275102A (en) Intermediates for diphenyl and phenyl pyridyl anti- histamines
US4966907A (en) 6-substituted 5-hydroxy-2,3-dihydrobenzofurans as inhibitors of leukotriene biosynthesis
CA2023776A1 (en) Leukotriene synthesis-inhibiting disubstituted (quinolin-2-yl-methoxy) phenylacetic acid derivatives
US5192771A (en) (quinolin-2-yl-methoxy)phenylacetic acid derivatives containing cyclic substituents
EP0531823A1 (en) Bicyclic carboxylic acid derivatives as anti-inflammatory agents
AU690258B2 (en) Substituted pyridine leukotriene B4 antagonists
EP0019440B1 (en) Benzimidazolone derivatives, process for their preparation and pharmaceutical compositions containing them
US4442102A (en) 1,5-Diphenylpyrazolin-3-one compounds, process and intermediates for preparation thereof and pharmaceutical compositions containing same
JPS60120866A (en) Novel carbostyryl derivative
CS226034B2 (en) Method of preparing pyridine derivatives
KR840001919B1 (en) Process for the preparation of substituted phenoxy-amino propanol derivatives
JPH0665115A (en) Acyclic tocotrienol homologue as remedy against hypercholesteremia and hyperlipemia
KR940003759B1 (en) Process for the preparation of 4-oh qunoline carboxylic acid derivatives
US5371227A (en) Quinoline derivatives, process for their preparation, and their therapeutic applications
NZ206001A (en) Aromatic compounds and pharmaceutical compositions
CA1247628A (en) Resorcinol ethers
JPH08508515A (en) Bicyclic Leucotriene Carboxylate B ▲ Lower 4 ▼ Antagonist
US5633258A (en) Pyridine compounds for treating leukotriene-related diseases

Legal Events

Date Code Title Description
MK14 Patent ceased section 143(a) (annual fees not paid) or expired