AU654051B2 - Pyridinol derivatives as medicaments - Google Patents

Pyridinol derivatives as medicaments Download PDF

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Publication number
AU654051B2
AU654051B2 AU26933/92A AU2693392A AU654051B2 AU 654051 B2 AU654051 B2 AU 654051B2 AU 26933/92 A AU26933/92 A AU 26933/92A AU 2693392 A AU2693392 A AU 2693392A AU 654051 B2 AU654051 B2 AU 654051B2
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AU
Australia
Prior art keywords
compound
formula
pyridin
tetrazolyl
hereinbefore defined
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AU26933/92A
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AU2693392A (en
Inventor
Kenneth John Murray
Roderick Alan Porter
Huter Douglas Prain
Brian Herbert Warrington
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings

Description

ii: f OPI DATE 03/05/93 AOJP DATE 08/07/93 APPLN. ID 26933/92 li lllII Illll PCT NUMBER PCT/GB92/01847 11 1 1111111 11111111 AU9226933 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 5 International Publication Number: WO 93/07137 C07D 401/04, 213/70 C07F 9/58, A61K 31/44 Al (43) International Publication Date: 15 April 1993 (15.04.93) (C07D 401/04, 257:00, 213:00) (21) International Application Number: PCT/GB92/01847 (74) Agent: THOMPSON, Clive, Corporate Patents, Smith- Kline Beecham, Mundells, Welwyn Garden City, Hert- (22) International Filing Date: 9 October 1992 (09.10.92) fordshire AL7 1EY (GB).
Priority data: (81) Designated States: AU, CA, JP, KR, US, European patent 9121651.5 11 October 1991 (11.10.91) GB (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, SE).
(71)Applicant (for all designated States except US): SMITH- KLINE BEECHAM PLC [GB/GB]; New Horizons Published Court, Brentford, Middlesex TW8 9EP With international search report.
(72) Inventors; and Inventors/Applicants (for US only) PORTER, Roderick, Alan [GB/GB]; PRAIN, Huter, Douglas [GB/GB]; Smithkline Beecham Pharmaceuticals, The Fryther, Welwyn, Hertfordshire AL6 9AR MURRAY, Kenneth, John [GB/GB]; Smithkline Beecham Pharmaceuticals, The Frythe, Welwyn, Hertfordshire AL6 9AR (GB).
WARRINGTON, Brian, Herbert [GB/GB]; Smithkline Beecham Pharmaceuticals, The Frythe, Welwyn, Hert- 6 5 4 I fordshire AL9 9AR (GB).
(54)Title: PYRIDINOL DERIVATIVES AS MEDICAMENTS (57) Abstract Trisubstituted pyridinol derivatives are described as agonists of a cyclic AMP-dependent protein kinase useful as medicaments.
1 WO 93/07137 PCT/GB92/01847 1 PYRIDINOL DERIVATIVES AS MEDICAMENTS The present invention relates to pyridinol derivatives, processes for their preparation, intermediates in their preparation, their use as medicaments and to pharmaceutical compositions comprising them.
The compounds of this invention are agonists of a cyclic AMP-dependent protein kinase (cA-PrK) (see J. Biol.
Chem., 1989, 264, 8443 8446) and are of use in combating such conditions where such agonism is thought to be beneficial. They are likely to have anti-proliferative, anti-aggregatory, cholesterol-lowering, smooth muscle relaxant, positive lusitropic, anti-allergic or antiinflammatory activities. They are likely to be useful in the treatment of cardiovascular diseases where there is component of diastolic failure, cancer, psoriasis, atheroschlerosis, thrombosis, chronic reversible lung disease such as asthma and bronchitis, allergic disease such as allergic asthma, allergic rhinitis and urticaria or gut motility disorders such as irritable bowel syndrome.
Accordingly the present invention provides compounds of the formula (1) a
R
R 0
R
Formula (1) or pharmaceutically acceptable salts thereof, wherein WO 93/07137 PCT/G B92/01 847 -2- RO is OH or a bioprecursor thereof,
R
1 is A 0 2 H, P(Z) (OH) (OR 2
SO
2 H, S0 3 H or optionally substituted in the 1-position by CH 2
CO
2 H or a bioprecursor thereof, AO is CH 2
CH
2
CH
2 CEF, CF 2
CR
3 (0R 4 CO or C(ORS) (OR 6
R
2 is phenyl, C3> 5 cycloalkyl, C 3 5 cycloalkylCl.
4 alkyl, or C 1 8 alkyl optionally substituted by C 1 4 alkoxy,
R
3 is H, methyl or ethyl,
R
4 is H or Cl 1 3 alkyl,
R
5 and R 6 are each C 1 3 alkyl or together form a 1,2ethanediyl group or l,3-propanediyl group, Z is 0 or S, Ra is halo or ll
X
1 is CH 2 0 or S,
Y
1 is C 1 6 alkyl or Ar, Ar is phenyl optionally substituted by one to three groups independently selected from halo, Cl- 6 alkyl,
C
2 6 alkenyl, Cl- 6 alkoxy, Cl- 6 P9lyfluoroalkyl or Cl- 6 polyfluoroalkoxy, or Ar is 1-naphthyl or 2-naphthyl, R is H, Cl- 6 alkyl or X 2 Arl wherein X 2 is a bond or ethenyl and 23--.68 PCT/GB9 21/0 184 13 JANUARY 1994 -3 Ar 1 is phenyl optionally substituted by one to three groups independently selected from C 1 6 alkyl, C 2 6 alkenyl, Clj 6 alkoxy, C 3 6 alkenyloxy, C 2 6 cYcloalkyl, C 2 6 cycloalkoxy, Clj 6 alkylthio, phenyl, phenylthio, benzyloxy, Cl 1 6 POlYfluoroalkyl, Cl 1 6 polyfluoroalkoxy, halo, N(R 7 2 or NHCOR 7 wherein R 7 is H or Cl 1 6 alkyl, or -X(CH2)nY attached to adjacent carbon atoms of the phenyl ring wherein X and Y are independently CR 2 or 0 and n is 1 to 3, wherein said Cl.
6 alkyl, C 2 6 alkenyl or Cl 1 6 alkoxy groups can be independently substituted by OH, Cl- 6 alkoxy, C 2 6 cycloalkyl,
N(R
7 2
COQ>R
7 or CON(R 7 2 or Ar' is 1-naphthyl optionally substituted in the 4-position by hydroxy or Cl 1 6 alkoxy, 2-naphthy. optionally substituted in the 1-position by hydroxy or C 1 6 alkoxy, 3-phenanthryl, 9phenanthryl, 2-quinolinyl, 4-quinolinyl, 3-thianaphthenyl or 2-benzofuranyl, with the proviso that Rl is not an unsubstituted group when RO is OH, Ra is Cl 1 4 alkyl, and R is R bOOR wherein Rb is C 1 6 alkyl, G 3 6 alkenyl, or Cl 1 4 alkyl substituted by 1 to 3 fluoro groups, and Rc is halo, Cj...
4 alkyl, Cl 1 4 alkoxy, Cj..
4 alkylthio, -NH 2 or
-NHC:OR
7 Bioprecursors of the groups RO and Rl are derivatives thereof which are convertible in vivo into the groups RO and Rl.
A suitable bioprecursor of the group RO is OR 8 wherein
R
8 is C1.
4 alkyl, aryl Cl 1 4 alkyl (for example phenyl C 1 4 alkyl such as benzyl), Cl 1 4 alkanoyl (for example acetyl), aryl
C
1 4 alkanoyl (for example phenyl Gj..
4 alkanoyl such as benzoyl), arylsuiphonyl (for example optionally substituted IUnited RInhgdomn Pazont Office SUBSTITUTE SHEET PCTIjtenational Application
I
PCTIGB 9 210 18 4 7 0l3 JANUARY 1994 i -3aphenylsuiphonyl or toluenesuiphonyl) or Cl 1 4 alkylsulphonyl (for example methylsuiphonyl).
When R1 is A 0 2 H a suitable bioprecursor is A 0 2
R
9 wherein R 9 is an ester-forming group.
When R1 is 2(Z) (OH) (OR 2 a suitable bioprecursor is 2(Z)(OR) 2 wherein Z and R 2 are as hereinbefore defined or P(Z) (OR 2 (OR1 0 wherein R 10 is an 0-protecting group.
United P~l Office SUBSTITUTE SHEET POT Iniccl.-t~ioflal Application u- WO 93/07137 PCT/GB92/01847 4 Suitable 0-protecting groups include pivaloyloxymethyl, propionyloxymethyl and pivalolyloxycarbonyloxymethyl.
When R 1 is l-(HO 2
CCH
2 )-5-tetrazolyl a suitable bioprecursor is 1-(R 9 0 2
CCH
2 )-5-tetrazolyl wherein R 9 is as hereinbefore defined.
When R 1 is 5-tetrazolyl, a suitable bioprecursor is a N-protected derivative thereof. Suitable N-protecting groups include pivaloyloxymethyl, propionyloxymethyl and pivalolyloxycarbonyloxymethyl.
Alternatively bioprecursors of the groups RO and R 1 are those formed when R 1 and RO are linked together to form a cyclic structure such that R 1 -RO is A 1 C0 2 or A20CH 2 0, in which Al is CH 2
CH
2
CH
2 CHF, CF 2
CR
3
(OR
4 CO or C(OR 5
)(OR
6
A
2 is P(Z)OR 2 or CR 3 (C0 2
R
9 and
R
2 to R 6
R
9 and Z are as hereinbefore defined.
Suitably RO is hydroxy or OR 8 preferably hydroxy.
Suitably R is H or Cl-6alkyl.
Suitably R is X 2 Arl as hereinbefore defined.
Suitably R 1 is AOCO 2 H or AOC0 2
R
9 Suitably R 1 is P(Z)(OH) (OR 2 or P(Z) (OR 2 2 Suitably R 1 is S0 2 H, SO 3 H or Suitably R 1 is 1-(HO 2
CCH
2 )-5-tetrazolyl or 1-
(R
9 0 2
CCH
2 WO 93/07137 PCT/GB92/01847 Suitably R 1 and RO are linked together such that R 1
-RO
is A 1 C0 2 Suitably R 1 and RO are linked together such that R 1
-RO
is A 2 0CH 2 0.
By the term alkyl is meant both straight- and branchedchain alkyl.
10 J By the term C-g 6 polyfluoroalkyl is meant a Cl-6alkyl group having at least one hydrogen replaced with fluoro, e.g.
CF
3 or CF 2
CF
2
H.
Suitably R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, 2-methoxyethyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclopropylmethyl.
Suitably R 3 is H, methyl or ethyl, preferably H or methyl.
Suitably R 4 is H, methyl, ethyl or propyl, preferably H or methyl.
Suitably R 5 and R 6 are independently methyl, ethyl or propyl, preferably together they form a 1,2-ethanediyl group.
Preferably Z is 0.
Suitably R 9 is Cl-4alkyl optionally substituted by hydroxy, e.g. 2-hydroxyethyl or aryl Cl-4alkyl (for example phenyl C 1 -4alkyl such as benzyl).
Suitably Ra is halo, for example iodo, bromo, or chloro, preferably bromo.
Suitably Ra is X 1 1 i '66 WO 93/07137 PCr/GB92/01847 -6- Suitably Y 1 is C1-6alkyl, for example methyl, ethyl, propyl, butyl, pentyl or hexyl.
Suitably Y 1 is Ar as hereinbefore defined.
Suitably Ar is 1-naphthyl or 2-naphthyl or phenyl optionally mono- or di-substituted by chloro.
Suitably Arl is phenyl optionally mono-substituted by a group as hereinbefore defined, for example in the 2,3, or 4 positions by C1- 6 alkyl, C1- 6 alkoxy, C 2 -6alkenyloxy, C1-6alkylthio, phenyl, phenylthio, benzyloxy, CF 3 halo or
NHCOR.
Suitably Arl is phenyl di-substituted by any groups as hereinbefore defined, for example in the or positions by groups independently selected from
C
2 6 alkenyl, C 1 -6alkoxy, C 2 -6cycloalkoxy, halo, -X(CH2)nY- or
C
1 -6alkoxyC 1 6 alkoxy.
Suitably Arl is phenyl trisubstituted by any groups as hereinbefore defined, for example in the or 3,4,5-positions by groups independently selected from
C
2 6 alkenyl, C 1 6 alkoxy or halo.
Suitably Arl is 1-naphthyl optionally substituted in the 4-position by hydroxy or C 1 -6alkoxy. Suitably Ar is 2naphthyl optionally substituted in the 1-position by hydroxy or C1-6alkoxy.
Suitably Arl is 3-phenanthryl or 9-phenanthryl.
Suitably Arl is 2-quinolinyl or 4-quinolinyl.
Suitably Arl is 2-benzofuranyl or 3-thianaphthenyl.
WO 93/07137 PCT/GB92/01847 -6- Suitably Y 1 is C1-6alkyl, for example methyl, ethyl, propyl, butyl, pentyl or hexyl.
Suitably Y 1 is Ar as hereinbefore defined.
Suitably Ar is 1-naphthyl or 2-naphthyl or phenyl optionally mono- or di-substituted by chloro.
Suitably Arl is phenyl optionally mono-substituted by a group as hereinbefore defined, for example in the 2,3, or 4 positions by C1- 6 alkyl, C 1 -6alkoxy, C 2 -6alkenyloxy,
C
1 6 alkylthio, phenyl, phenylthio, benzyloxy, CF 3 halo or
NHCOR.
Suitably Arl is phenyl di-substituted by any groups as hereinbefore defined, for example in the or positions by groups independently selected from
C
2 -6alkenyl, C 1 -6alkoxy, C 2 -6cycloalkoxy, halo, -X(CH2)nY- or
C
1 -6alkoxyC1- 6 alkoxy.
Suitably Arl is phenyl trisubstituted by any groups as hereinbefore defined, for example in the or 3,4,5-positions by groups independently selected from
C
2 6 alkenyl, C1- 6 alkoxy or halo.
Suitably Arl is 1-naphthyl optionally substituted in the 4-position by hydroxy or C1- 6 alkoxy. Suitably Ar is 2naphthyl optionally substituted in the 1-position by hydroxy or C 1 6 a:coxy.
Suitably Arl is 3-phenanthryl or 9-phenanthryl.
Suitably Arl is 2-quinolinyl or 4-quinolinyl.
Suitably Arl is 2-benzofuranyl or 3-thianaphthenyl.
WO 93/07137 PCT/GB92/01847 Examples Of Cl 1 6 alkoxy include methoxy, ethoxy, propoxy, butoxy, or pentyloxy.
Examples Of C 1 6 alkyl include methyl, ethyl, propyl, butyl, isobutyl or pentyl.
Examples of halo include fluoro, chioro, bromo or iodo.
Particular compounds of this invention include (2-naphthylthio) (5-tetrazolyl)pyridin-2 (lH) one, 3- (l-carboxymethyl-5-tetrazolyl) -6-methyl-5- (2-naphthylthio) pyridin-2 (lH) -one, n-propyl- (2-naphthylthio) -2-oxo-1, 2-dihydro-3-pyridyl] phosphonate, 6-met.hyl-5-phenylthio-3- (5-tetrazolyl)pyridin-2 (lH) -one, (4-chlorophenylthio) -6-methyl-3- (5-tetrazolyl) pyridin- 2 (lH) -one, E-6- (2-phenylethenyl) -5-phenylthio-3- (5-tetrazolyl) pyridin- 2 (1H) -one, 3-carboxymethyl-6-methyl-5- (phenylthio)pyridin-2 (lH) -one, 6-phenyl-5-phenylthio-3- (5-tetrazolyli pyridin-2 (lH) -one, (3-chlorophenylthio) -6-methyl-3- (5-tetrazclyl) pyridin- 2 (1H) -one, (2-chlorophenylthio) -6-methyl-3- 2 (lH)-one, WO 93/07137 PCr/GB92/01 847 -8- 4-dichlorophenylthio) -6-methyl-3- (5-tetrazolyl) pyridin- 2 (1H) -one, 5-n-butylthio-6-methyl-3- (5-tetrazolyl)pyridifl-2 (1H)-one, I ~5-n-butylthio-6- (4-methoxy-3-propoxypeyl) tetrazolyl)pyridin-2 (lH) -one, 5-benzyl-6-phenyl-3- (5-tetrazolyl) pyridin-2 (1H) -one, (2-naphthyloxy) -6-phenyl-3- (5-tetrazolyl) pyridin-2 (1H) -one, I (2-naphthyl) -5-phenylthio-3- (5-tetrazolyl)pyridin-2 (1H) (2-naphthylthio) -6-phenyl-3- (5-tetrazolyl)pyridin-2 one, 5-n-butylthio-6-(3, 4-dimethoxyphenyi)-3-(5-tetrazoly1)pyridin-2 (1H) -one, 3- [6-methyi-5- (2-napthylthio) -2-oxo-1, 2-dihydro-3-pyridyi] propionic acid, 5-phenylthio-6- (4-rethoxy-3-propoxyphel) (5-tetrazolyl) pyridin-2 (iH) -one, 5-methylthio-6- (4-methoxy-3-propoxyphenyi) (5-tetrazolyl) pyridin-2 (1H) -one, 5-ethylthio-6- (4-methoxy-3-propoxyphenyi) (5-tetrazolyl) pyridin-2 (1H) -one, 5-bromo-6- (4-methoxy-3-propoxyphenyi) (5-tetrazolyl) pyridin-2 (1H) -one, 6-(3,4-dimethoxyphenyl)-5-pentyl-3-(5-tetrazolyl)pyridin- 2(lH)-one, 6-(2-naphthyl)-5-phenoxy-3-(5-tetrazolyl)pyridin-2(1H)-one, 5-n-butylthio-6-[3-(E-l-propenyl)-4-methoxyphenyl]-3-(5tetrazolyl)pyridin-2(1H)-one, ethyl (5-phenylthio-2-oxo-l,2-dihydro-3-pyridyl)phosphonate, 5-n-butylthio-6-(4-methoxy-3-n-propylphenyl)-3-(5tetrazolyl)pyridin-2(1H)-one, or 5-n-butylthio-6-[3-(E-l-propenyl)-4-methoxyphenyl]-3-(5tetrazolyl)pyridin-2(1H)-one, and pharmaceutically acceptable salts thereof.
This invention covers all tautomeric, geometric and optical isomeric forms of compounds of formula In particular when RO is hydroxy the compound can exist in its keto tautomeric form a a R R R R tY fi^ 1 N 1 NH R R 0 R O Compounds of the formula can form pharmaceutically acceptable base addition salts with metal ions, such as alkali metals for example sodium or potassium, or with an ammonium ion.
In order to use a compound of the formula or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in i 4 1 Li 4 WO 93/07137 PCT/GB92/01847 23 WO 93/07137 PCT/GB92/01847 10 accordance with standard pharmaceutical practice as a pharmaceutical composition.
Compounds of formula and their pharmaceutically acceptable salts may be administered in standard manner for the treatment of the indicated diseases, for example orally, sublingually, parenterally, transdermally, rectally, via inhalation or via buccal administration.
Compounds of formula and their pharmaceutically acceptable salts which are active when given orally or via buccal administration can be formulated appropriately in dosage forms such as liquids, syrups, tablets, capsules and lozenges. An oral liquid formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include starch, celluloses, lactose, sucrose and magnesium stearate. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil or solubilising agent, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, 2pyrrolidone, cyclodextrin, arachis oil, or sesame oil.
i'i 8 WO 93/07137 PC7/GB92/01847 11 A typical suppository formulation comprises a compound of formula or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane, or are in the form of a powder for insufflation.
Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose.
Each dosage unit for oral administration contains suitably from 0.001 mg/Kg to 30 mg/Kg, and preferably from 0.005 mg/Kg to 15 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.001 mg/Kg to mg/Kg, of a compound of formula or a pharmaceutically acceptable salt thereof calculated as the free acid.
The daily dosage regimen for oral administration is suitably about 0.001 mg/Kg to 120 mg/Kg, of a compound of formula or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, for example about 0.005 mg/Kg to 10 mg/Kg, of a compound of the formula or a pharmaceutically acceptable salt thereof calculated as the free acid. The active f 1 1^ T WO 93/07137 PCT/GB92/01847 12 ingredient may be administered as required for example from 1 8 times a day or by infusion. The compositions of the invention are agonists of a cA-PrK and are of use in combating such conditions where such agonism is thought to be beneficial. Such conditions can be treated by administration orally, sublingually topically, rectally, parenterally or by inhalation. For administration by inhalation dosages are controlled by a valve, are administered as required and for an adult are conveniently in the range 0.1 5.0 mg of a compound of the formula or a pharmaceutically acceptable salt thereof.
The compounds of this invention may be co-administered with other pharmaceutically active compounds, for example in combination, concurrently or sequentially. Conveniently the compounds of this invention and the other active compound or compounds are formulated in a single pharmaceutical composition. Examples of compounds which may be included in pharmaceutical compositions with the compounds of the formula are bronchodilators such as sympathomimetic amines for example isoprenaline, isoetharine, sulbutamol, phenylephrine and ephedrine or xanthine derivatives for example theophylline and aminophylline, anti-allergic agents for example disodium cromoglycate, histamine Hl-antagonists, drugs used in the treatment of cancer such as those which inhibit the synthesis of or inactivate DNA, for example methotrexate, fluoracil, cisplatin, actinomycin D, antiatherschlerotic agents for example cholesterol lowering drugs such as HMGCoA reductase inhibitors, bile acid sequestrants, drugs for the treatment of psoriasis, for example retinoids, anthralin, anti-inflammatories for example cortiscosteroids, non-steroid anti-inflammatories such as aspirin, antithrombotics for example dipyridamole, or fibrinolytic agents.
In another aspect the present invention provides a process for the preparation of compounds of the formula (1) or pharmaceutically acceptable salts thereof, which process comprises a) for compounds wherein R 1 is AOC0 2 H or AOC0 2
R
9 and i) AO is CR 3
OR
4 reacting in the presence of a strong base a compound of the formula
R
R
ON
11 Formula (2) wherein R 11 is methyl and R and Ra are as hereinbefore defined, with a compound of the formula
R
3 COC0 2
R
9 wherein R 3 and R 9 are as hereinbefore defined to form a compound of the formula
R
R
12ON R 21Y
OR
Formula (4) i i 4
I
-4 1 j r WO 93/07137 PCT/GB92/01847
I
27 WO 93/07137 PCT/GB92/01847 14 wherein R 12 is CR 3 (OH)C0 2
R
9 and R, R 3
R
9
R
11 and Ra are as hereinbefore defined and thereafter optionally reacting with a C1- 3 alkylating agent to form the corresponding compound wherein R 12 is CR 3 (OC1- 3 alkyl)C0 2
R
9 ii) AO is CO, reacting in the presence of a strong base a compound of the formula as hereinbefore defined with a compound of the formula
R
9 0 2 CC0 2
R
9 wherein R 9 is as hereinbefore defined to form a compound of the formula wherein R 12 is COCO 2
R
9 and R, R 9
R
31 and Ra are as hereinbefore defined, iii) AO is CH(OH), reacting a compound of the formula wherein R 12 is COC02R 9 and R, R 9
R
1 1 and R a are as hereinbefore defined with a reducing agent to form the corresponding compound wherein R 12 is CH(OH)CO 2
R
9 iv) AO is CH 2 reacting a compound of the formula wherein R 12 is COCO 2
H
or COCO 2
R
9 and R, R 9
R
1 1 and Ra are as hereinbefore defined with a suitable reducing agent to form the corresponding compound wherein R 12 is CH 2
CO
2
H,
v) AO is C(OR 5
(OR
6 reacting a compound of the formula wherein R 12 is COC0 2
R
9 and R, R 9
R
1 1 and R a are as hereinbefore defined with a
C
1 -3alcohol, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound wherein R 12 is C(OR 5
)(OR
6 )C0 2
R
9 vi) AO is CF 2 reacting a compound of the formula wherein R 12 is COC0 2
R
9 and R, R 9
R
1 1 and Ra are as hereinbefore defined with a i WO 93/07137 PCT/GB92/01847 15 fluorinating agent to form the corresponding compound wherein
R
11 is CF 2
CO
2
R
9 or vii) AO is CHF, reacting a compound of the formula wherein R 12 is CH(OH)C0 2
R
9 and R, R 9
R
11 and Ra are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R 12 is CHFCO 2
R
9 and thereafter optionally converting the group OR 11 into OH converting the group AOC0 2
R
9 into AOC0 2 H; or b) for compounds wherein R 1 is CH 2 C0 2
H,
converting a compound of the formula a
R
r R 130 N
OH
Formula (6) wherein R 13 is acetyl and R, and Ra are as hereinbefore defined into the corresponding compound wherein R 13 is
CH
2
CO
2 H; or c) for compounds wherein R 1 is CH 2
CH
2
CO
2 H or CH 2
CH
2
CO
2
R
9 hydrogenating a compound of the formula wherein R 13 is
CH=CHCO
2 H or CH=CHCO 2
R
9 and thereafter optionally converting the group CH 2
CH
2 C0 2
R
9 into CH 2
CH
2
CO
2 H; or
I
::l li~r~:rln -e r j WO 93/07137 PCT/GB92/01847 Iaaiac 29 United vor Pt SUBSTITUTE SHEET PCT Inieiizj-iaio fl PAp icpliio j i ii n i WO 93/07137 PCT/GB92/01847 16 d) for compounds wherein R 1 is P(O)(OH)(OR2), hydrolysing a compound of the formula wherein R 13 is P(O)(OR 2 2 and R, R 2 and R a are as hereinbefore defined; or e) for compounds wherein R 1 is P(S)(OH)(OR 2 converting a compound of the formula wherein R 13 is P(O)(NHR 14
)(OR
2 and R 14 is phenyl or C 2 6 1 -4alkyl and R, and R a are as hereinbefore defined into the corresponding compound wherein
R
13 is P(S) (OH) (OR 2 or f) for compounds where R 1 is SO 3
H,
reacting in the presence of a strong base a compound of the formula as hereinbefore defined with sulphuryl chloride or a chemical equivalent thereof and optionally converting the group OR 11 into OH; or g) for compounds wherein R 1 is SO 2
H,
reacting in the presence of a strong base a compound of the formula as hereinbefore defined with sulphur dioxide and optionally converting the group OR 11 into OH; or h) for compounds wherein R 1 is reacting a compound of the formula wherein R 12 is cyano or a compound of the formula wherein R 13 is cyano with an azide salt; or i) for compounds wherein R 1 is 1-(HO 2
CCH
2 or 1-(R 9 0 2
CCH
2 )-5-tetrazolyl, reacting a compound of the formula wherein R 13 is 5-tetrazolyl with a compound of the formula i
LCH
2
CO
2
R
9 wherein L is a leaving group and R 9 is as hereinbefore defined and thereafter optionally converting the group CC to C02H; or a ,2R9 i :i i i 1~ -1 -Ji: WO 93/07137 PCT/GB92/01847 17 j) for compounds wherein Ra is halo, reacting a compound of the formula (8)
R
O is N
R
OH
Formula (8) wherein R 15 is a group R1 as hereinbefore defined or a precursor thereof, and R is as hereinbefore defined, with a suitable halogenating agent, and thereafter if necessary converting a precursor of R 1 to R1; and optionally thereafter forming a bioprecursor of RO and/or R 1 forming a pharmaceutically acceptable salt.
Suitably a compound of the formula is reacted with a strong base such as lithium diisopropylamide, or a C1- 4 alkyl lithium or aryl lithium such as mesityl lithium in an organic solvent such as tetrahydrofuran, diethylether or dimethoxyethane with cooling (-1000 0°C) to form the anion thereof. The strong base may be formed in situ, for example by the addition of a Cl-4alkyl lithium e.g. methyllithium followed by a catalytic quantity of diisopropylamine.
The anion of a compound of the formula is suitably reacted with, a compound of the formula or a compound of the formula in an organic solvent such as tetrahydrofuran, diethylether or dimethoxyethane with cooling (-100° to 0 C) to form a compound of the formula wherein R 12 is
CR
3 (OH)C0 2
R
9 or COCO 2
R
9 respectively. A suitable compound WO 93/07137 PCT/GB92/01847 -18of the formula is ethylpyruvate, or ethyl glyoxylate or a chemical equivalent thereof and a suitable compound of the formula is diethyloxalate.
A compound of the formula wherein R 12 is
CR
3 OH)CO2R 9 is suitably reacted with a C1- 3 alkylating agent such as iodomethane, iodopropane or dimethylsulphate in the presence of a base such as sodium hydride or potassium hydroxide in an organic solvent such as dimethylformamide or dimethylsulphoxide at elevated 30 80 0 C) or preferably ambient temperature to form the corresponding compound wherein R 12 is CR 3 (0C 1 -3alkyl)C0 2
R
9 When potassium hydroxide is used as base the C0 2
R
9 group may be directly converted to carboxy.
A compound of the formula wherein R 12 is COC0 2
R
9 is suitably reacted with a reducing agent such as sodium borohydride, or diisobutylaluminium hydride in an organic solvent such as dichloromethane, a C 2 61 4 alcohol e.g.
ethanol, or acetic acid or mixtures thereof at ambient or elevated temperature 30 80 0 or with cooling (e.g.
0 5 0 C) to form the corresponding compound wherein R 12 is CH(OH)C0 2
R
9 A compound of the formula wherein R 12 is COC0 2 H or COC0 2
R
9 is suitably reacted with a reducing agent such as a zinc amalgam in hydrochloric acid in the absence of a solvent or in a solvent such as ethanol, acetic acid or dioxan and hydrogen chloride gas at ambient or elevated temperature 40-100°C) to form the corresponding compound wherein
R
12 is CH 2
CO
2 H. Under these reaction conditions the C0 2
R
9 group is converted to carboxy.
A compound of the formula wherein R 12 is COC0 2
R
9 is suitably reacted with a C1- 3 alcohol, 1,2-ethanediol or 1,3propanediol in the presence of an acid catalyst such as paratoluenesulphonic acid, concentrated sulphuric acid or u I anhydrous hydrogen chloride, at ambient or elevated temperature to form the corresponding compound wherein R 12 is
C(OR
5
(OR
6
)CO
2
R
9 A compound of the formula wherein R 12 is COC0 2
R
9 or
CHOHCO
2
R
9 is suitably reacted with a fluorinating agent such as diethylaminosulphur trifluoride in an organic solvent such as a halohydrocarbon or an ether such as glyme, or THF at ambient or elevated temperature 30-60 0 C) to form the corresponding compound where R 12 is CF 2
CO
2
R
9 or CHFCO 2
R
9 respectively.
A compound of the formula wherein OR 11 is methoxy can suitably be converted to the corresponding compound wherein OR 11 is hydroxy by reaction with sodium iodide and chlorotrimethylsilane in an organic solvent such as acetonitrile, or a halohydrocarbon e.g. dichloromethane or chloroform at elevated 30 80 0 C) or preferably ambient temperature. This method is particularly suitable for preparing compounds of the formula wherein R 1 is A 0 C0 2
R
9 since the ester-forming group R 9 is not hydrolysed under the reaction conditions. Another method utilises sodium thiomethoxide in an organic solvent such as dimethylformamide at an elevated temperature for example 40 120 0 C. The more forcing conditions of this method are suitable for preparing compounds of formula wherein R 1 is ACOC 2
H.
A compound of the formula wherein R 12 is AOC0 2
R
9 can suitably be converted to the corresponding compound wherein R 12 is ACO 2 H by reaction with an aqueous base such as sodium or potassium hydroxide at ambient or elevated temperature 40 1200). This method is particularly suitable for preparing compounds of the formula wherein RO is methoxy since the OR 11 group is not hydrolysed.
Another hydrolysis method utilises aqueous acid such as concentrated hydrochloric acid at an elevated temperature WO9/3 PC--B 2/1 4 WO 93/07137 PCT/GB92/01847 33 Suitably Arl is 2-benzofuranyl or 3-thianaphthenyl.
i J WO 93/07137 PC/GB92/01847 20 40 120 0 C) which provides directly compounds of the formula wherein RO is hydroxy and R 1 is AOC0 2
H.
Suitably a compound of the formula wherein R 13 is acetyl is converted to the corresponding compound where R 13 is CH 2
CO
2 H by reaction with sulphur and morpholine at elevated temperature 50 200 0 followed by hydrolysis with an aqueous base such as sodium hydroxide at elevated temperature, preferably at the reflux temperature of the reaction mixture.
Suitably a compound of the formula wherein R 13 is CH=CHC0 2 H or CH=CHCO 2
R
9 is hydrogenated (suitably 1 to atmospheres of hydrogen) in the presence of a suitable catalyst e.g. a rhodium catalyst such as tris(triphenylphosphine)rhodium chloride, in a suitable solvent such as a C1- 4 alkanol or tetrahydrofuran at ambient or elevated temperature 40 100°C), preferably ambient temperature.
A compound of the formula wherein R 13 is CH=CHCO 2
R
9 is suitably prepared by reacting a compound of formula (6) wherein R 13 is CHO with a suitable Wittig reagent such as (Ph) 3
P=CHCO
2
R
9 in an organic solvent such as toluene, or tetrahydrofuran at an elevated temperature 50 1500C), conveniently at the reflux temperature of the reaction mixture. If desired the compound of formula wherein R 13 Sis CHCHC 2
R
9 can be converted to the corresponding compound where R 13 is CH=CHCO 2 H as hereinbefore described.
A compound of the formula where R 13 is CHO is suitably prepared by reacting the corresponding compound wherein R 13 is cyano with a suitable reducing agent such as diisobutylaluminium hydride followed by acidic aqueous workup.
i SJ i WO 93/07137 PCT/GB92/01847 -21- Suitably a compound of the formula wherein R 13 is
P(O)(OR
2 2 is hydrolysed by reaction with an aqueous base such as sodium hydroxide optionally in a cosolvent such as a
C
1 4 alcohol at an elevated temperature 40-100 0
C),
preferably at the reflux temperature of the reaction mixture.
Suitably a compound of the formula wherein R 13 is P(0)(NHR 14
)(OR
2 is converted to the corresponding compound wherein R 9 is P(S) (OH) (OR 2 by reaction with a strong base such as sodium hydride in an organic solvent such as dimethoxyethane at ambient or elevated temperature, 100 0 C) followed by reaction with carbon disulphide.
Suitably the anion of a compound of the formula (2) prepared as hereinbefore described is reacted with sulphuryl chloride or a chemical equivalent thereof or with sulphur dioxide in an organic solvent such as tetrahydrofuran with cooling (-1000 0°C) to form after aqueous work-up a compound of the formula wherein R 12 is S0 3 H or SO 2
H
respectively and OR 11 is methoxy which if desired can be converted to the couresponding compound wherein OR 11 is hydroxy as hereinbefore described.
A compound of the formula wherein R 11 is cyano or a compound of the formula wherein R 13 is cyano is suitably reacted with an azide salt such as ammonium, sodium, potassium or aluminium azide in an organic solvent such as dimethylformamide, dimethylsulphoxide, N-methylpyrrolidone or tetrahydrofuran at an elevated temperature e.g. 40 200 0
C,
preferably at 100-150 0 C to form the corresponding tetrazolyl compound.
Suitably a compound of the formula wherein R 13 is is reacted with a compound of the formula in an organic solvent such as dimethylformamide or acetonitrile in the presence of a base such as potassium or sodium 2 m_1: ^L~ :i WO 93/07137 PCT/GB92/01847 22 bicarbonate at ambient or elevated temperature 160 0
C)
Suitably a compound of the formula wherein R 13 is l-(R 9 0 2
CCH
2 )-5-tetrazolyl is hydrolysed by reaction with an aqueous base such as sodium hydroxide optionally in a cosolvent such as a Cl-4alcohol at an elevated temperature 40 100 0 preferably at the reflux temperature of the reaction mixture.
A compound of the formula is suitably reacted with a halogenating agent, for example a brominating agent such as N-bromosuccinimide in an organic solvent such as dimethylformamide or dimethylsulphoxide, at ambient or elevated temperature, e.g. 40-200 0 C, conveniently at the reflux temperature of the reaction mixture. An example of a bioprecursor of the group R 1 is cyano, which can be converted as hereinbefore described to If desired a compound of the formula wherein R 1 is
AOCO
2 H can be converted to the corresponding compound wherein
R
1 is ACOC 2
R
9 by reaction with a compound R90H wherein R 9 is as hereinbefore defined.
A compound of the formula wherein RO is OH can be converted to the corresponding compound where RO is OR 8 by reaction with R 8
L
1 wherein R 8 is as hereinbefore defined and
L
1 is a leaving group such as halo e.g. bromo, chloro, iodo.
If desired a compound of the formula wherein R 1 is
P(Z)(OR
2 can be converted to the corresponding compound wherein R 1 is P(Z)(OR 2
)(OR
1 0 by reaction with a suitable Oprotecting agent in standard manner. For example the compound can be reacted with a pivalolyloxymethyl halide.
A compound of the formula wherein R 1 is can be reacted with a suitable N-protecting agent in a I~ -CCICIC~ i i i i WO 93/07137 PCT/GB92/01847 23 standard manner, for example with a pivalolyloxymethyl halide.
A compound of the formula wherein R 1
-R
0 is A 1
CO
2 is suitably prepared by heating a compound of the formula (1) wherein R 1 is A1CO 2 H and RO is OH with a dehydrating agent such as acetic anhydride, at an elevated temperature 200 0 preferably at the reflux temperature of the reaction mixture.
A compound of the formula wherein R 1
-R
0 is A20CH20 is suitably prepared by reacting a compound of the formula wherein R 1 is A20H and RO is OH with a dihalomethane such as diiodo or dibromomethane in the presence of silver carbonate in an organic solvent such as dimethylformamide at an elevated temperature 40 120 0
C).
A compound of the formula is suitably prepared by reacting a compound of the formula wherein R 13 is hydrogen with an O-methylating agent such as dimethylformamide dimethylacetal in dimethylformamide or trimethylphosphite at an elevated temperature 40 120 0 C) or with iodomethane and silver carbonate in toluene or chloroform.
A compound of the formula wherein R is X 2 Arl, X 2 is ethenyl and R 13 is cyano is suitably prepared by reaction of the corresponding compound wherein R is methyl with ArlCHO in the presence of a base such as tetrabutylammonium fluoride in an organic solvent such as tetrahydrofuran followed by workup and treatment of the resulting compound with a dehydrating agent such as acetic anhydride in acetic acid at ambient or elevated temperature 40 150 0 preferably the reflux temperature of the reaction mixture.
ii 'i t WO 93/07137 PCT/GB92/01847 -24 A compound of the formula wherein Ra is X 1 y 1
R
13 is cyano, acetyl or hydrogen is suitably prepared by reaction of a compound of the formula (9) 1 1 (9) Y X CCOR 2
CHL
with a compound of the formula
R
16
CH
2
CONH
2 wherein R 1 6 is cyano, acetyl or hydrogen respectively, and L 2 is a displaceable group and X 1 yl and R are as hereinbefore defined.
Suitably L 2 in a compound of the formula is hydroxy or a derivative thereof for example L 2 is protected hydroxy such as silyloxy, an acid residue (for example Cl-6alkanoyloxy) or an ether residue (for example methoxy or ethoxy). Alternatively L 2 is a secondary amino group, for example di-C 1 -6alkylamino such as dimethylamino or a cyclic amino group such as piperidino, pyrrolidino or morpholino.
Preferably L 2 is hydroxy or dimethylamino.
Suitably an alkali metal sodium) salt of a compound of the formula wherein L 2 is hydroxy is treated with a compound of the formula (10) under mildly alkaline aqueous conditions, for example in water in the presence of piperidine and glacial acetic acid, at an elevated temperature 30 200°C), preferably at the reflux temperature of the reaction mixture.
Alternatively a compound of the formula wherein L 2 is a secondary amino group, for example dimethylamino, is treated with a compound of the formula (10) in a suitable 1 WO 93/07137 PCT/GB92/01847 25 solvent such as dimethylformamide, a C1- 4 alkanol or pyridine at an elevated temperature e.g. (30 200 0 preferably at the reflux temperature of the reaction mixture optionally in the presence of a base such as pyridine or an alkali metal alkoxide, e.g. sodium methoxide.
Compounds of the formula wherein L 2 is hydroxy can suitably be prepared by reaction under basic conditions of a compound of the formula (11)
Y
1
X
1
CH
2 COR (11) wherein R, X 1 and Y 1 are as hereinbefore defined, with a compound of the formula HCOL 3 wherein L 3 is a leaving group.
Suitably L 3 is ethoxy or methoxy. Conveniently a solution of a compound of the formula (11) and a compound of the formula HCOL 3 in a suitable organic solvent such as diethyl ether is treated with a suitable base such as an alkali metal alkoxide, e.g. sodium methoxide at ambient temperature. The resulting reaction mixture is preferably extracted with water and the aqueous extract which contains the alkali metal salt of a compound of the formula (9) wherein L 2 is hydroxy is then treated with a compound of the formula (10) as hereinbefore described.
Compounds of the formula wherein L 2 is a secondary amino group dimethylamino) can suitably be prepared by reacting a compound of the formula (11) with a compound of the formula HC(OR 17 2
L
2 wherein R 17 is C 1 -4alkyl and L 2 is a secondary amino group (for example HC(OR 1 7 2
L
2 is N,Ndimethylformamide dimethyl or diethyl acetal). Alternatively a compound of the formula (11) can be reacted with a compound of the formula HC(L 2 3 (for example tris dimethylaminomethane).
N.R WO 93/07137 PCT/GB92/01847 26 A compound of the formula (11) wherein X 1 is 0 or S is suitably prepared by reaction of a compound of the formula (12)
Y
1
X
3 H (12) I wherein X 3 is 0 or S and yl is as hereinbefore defined with a compound of the formula (13)
RCOCH
2
L
4 (13) wherein R is as hereinbefore defined and L 4 is a leaving group such as halo.
Suitably a compound of the formula (12) and a compound of the formula (13) in a suitable organic solvent such as dimethylformamide are treated with a base such as potassium carbonate at ambient or elevated temperature 40-160 0
C)
A compound of the formula (11) wherein X 1 is S and Y 1 t is C1- 6 alkyl can also be prepared by reacting a comround of Sthe formula (13) with sodium or potassium thioacetate followed by treatment of the intermediate with a base such as sodium methoxide and an alkylating agent such as a Cl-6alkyl halide, e.g. iodomethane or iodoethane in a solvent such as dimethylformamide or methanol.
A compound of the formula wherein R 13 is acetyl can also be prepared by reacting a compound of the formula (6) wherein R 13 is cyano with methyl lithium followed by aqueous work up with for example dilute hydrochloric acid or aqueous ammonium chloride.
A compound of the formula wherein R 13 is hydrogen 35 can also be prepared by heating a compound of formula (11) as hereinbefore defined with a C 1 -4alkyl propiolate (such as methyl propiolate) and ammonia in a solvent such as a L n R} BY 1 WO 93/07137 PCT/GB92/01847 -27-
C
1 -4alkanol in a pressure vessel at elevated temperature 200 0 C) preferably at 100 0
C.
Alternatively a compound of the formula wherein R 13 is hydrogen can be prepared by reacting a compound of the formula wherein R 13 is cyano with orthophosphoric acid at an elevated temperature, e.g. 50 200 0
C.
Alternatively a compound of the formula wherein X 1 is 0 or S, R is H or C 1 -6alkyl and R 13 is hydrogen or cyano can be prepared by reaction of a compound of the formula (14)
L
A
ON
OH
Formula (14) wherein L 5 is halo, for example bromo, A is H or C1-6alkyl and B is H or cyano, with a compound of the formula (12) as hereinbefore defined or a chemical equivalent thereof in a solvent such as dimethylformamide or N-methylpyrrolidinone or quinoline in the presence of a base such as potassium carbonate or pyridine at ambient or elevated temperature 40 160 0 An example of a chemical equivalent of a compound of the formula (12) is a copper salt such as a bis-
(C
1 -6alkylthio) copper salt.
A compound of formula wherein R 12 is cyano is suitably prepared by reacting the anion of a compound of formula wherein R, R a and R 11 are as hereinbefore defined with dimethylformamide with cooling -80 to 10 0
C),
I
1 1 WO 93/07137 PCT/GB92/01847 28 followed by ambient temperature and aqueous work-up. The resulting compound of formula wherein R 1 2 is carboxaldehyde is treated with hydroxylamine hydrochloride and sodium acetate in a suitable solvent such as ethanol or methanol at elevated temperature, e.g. 40-100 0 C, preferably at the reflux temperature of the reaction mixture followed by dehydrating the product obtained for example by heating with acetic anhydride.
A compound of the formula wherein R 13 is cyano or acetyl and R, and Ra are as hereinbefore defined can be suitably prepared by reaction of a compound of formula (4) wherein R 1 2 is cyano or acetyl and R, Rll 1 and Ra, X 1 and yl are as hereinbefore defined with a demethylating agent such as sodium iodide/chlorotrimethylsilane in the absence of solvent or in an organic solvent such as acetonitrile or chloroform at an elevated temperature 40 to 100 0 C) or at ambient temperature.
A compound of the formula wherein R 1 3 is (OR 2 2 can be prepared by treating a compound of the formula (2) wherein Ro is P(O)(OR 2 2 with a strong base such as lithium diisopropylamide in an organic solvent such as tetrahydrofuran with cooling -100-0 0
C).
A compound of the formula wherein R 11 is P(O)(OR 2 2 is suitably prepared by treating a compound of the formula wherein R 1 3 is hydrogen with a compound of the formula
L
6 p(0)(OR 2 2 wherein L 6 is a leaving group and R 2 is as hereinbefore defined with a base such as diisopropylethylamine.
Suitably L 6 is halo, for example chloro or bromo.
WO 93/07137 PCT/GB92/01847 29 A compound of formula wherein R 11 is P(O)(OR 2 2 can also be prepared by treating a compound of the formula (6) wherein R 13 is hydrogen with a compound of the formula (16): HP(0) (OR 2 2 (16) wherein R 2 is as hereinbefore defined in the presence of an amine base such as triethylamine, and carbon tetrachloride.
Alternatively, a compound of the formula wherein
R
13 is P(O) (OR 2 2 is suitably prepared by treating a compound of the formula wherein R 13 is hydrogen with a compound of the formula (15) in the presence of a strong base such as lithium diisopropylamide in an organic solvent such as tetrahydrofuran with cooling -100-0 0 C) without isolation of the intermediate compound of the formula (2) wherein R 11 is P(O) (OR 2 2 A compound of formula wherein R 13 is hydrogen is suitably prepared by demethylating a compound of formula (2) as hereinbefore defined. Suitably a compound of formula (2) is treated with boron tribromide in an organic solvent such as dichloromethane or toluene with cooling -80 to 10 0
C)
followed by ambient temperature and aqueous work-up. Or a compound of formula is treated with sodium iodide and chlorotrimethylsilane at ambient or elevated temperature 40-80°C) conveniently ambient temperature in a solvent such as acetonitrile or dichloromethane.
A compound of the formula wherein R 13 is
P(O)(NHR
14
)(OR
2 can be prepared by reaction of a compound of the formula wherein R 1 3 is P(0) (OH) (OR 2 with carbon tetrachloride, triphenylphosphine and aniline or a Cl-4alkylamine in an organic solvent such as pyridine at ambient temperature or with cooling -10 to 5 0
C).
Alternatively a compound of the formula where R 13 is
P(O)(OH)(OR
2 can be reacted with dimethylformamide and
S'
1 'I 1 .r it WO 93/07137 PCT/GB92/01847 30 oxalyl chloride in an organic solvent such as a halo hydrocarbon e.g. dichloromethane at ambient temperature, followed by reaction with aniline or a C1-4alkylamine preferably with cooling (-10 to 5 0
C).
A compound of the formula wherein Ra is SY 1 can be 7
L
R
OYN
11
OR
Formula (17) wherein L 7 is halo such as bromo or iodo, R 11 is methyl and R is as hereinbefore defined with a compound of the formula (12) or a chemical equivalent thereof wherein X 3 is S and Y 1 is as hereinbefore defined. An example of a suitable chemical equivalent is a tin complex such as phenyltributyltin sulphide when Y 1 is phenyl which can be reacted with a compound of the formula (17) according to the method of Kosugi et al as noted in Example 27 hereinafter.
Pharmaceutically acceptable base addition salts of the compounds of the formula may be prepared by standard methods, for example by reacting a solution of the compound of the formula with a solution of the base.
The following biological test methods, data and Examples serve to illustrate this invention.
Cyclic-AMP Protein Kinase (cA-PrK) Agonist Activity :t 1 i. T^
I
WO 93/07137 PCT/GB92/01847 -31 Type II cA-PrK was prepared from the cardiac muscle of a cow. The supernatant from a muscle homogenate (3 mis of mM potassium phosphate, 1 mM EDTA per g tissue) was applied to a column of DEAE-cellulose equilibrated with the homogenisation buffer and the type II cA-PrK was eluted with homogenisation buffer containing 350 mM sodium chloride (Rannels et al., 1983, Methods Enzymol., 99, 55-62).
Type II cA-PrK was assayed for phosphotransferase activity by incubating the enzyme at 30 0 C for 5 minutes with [y- 32 p]-adenosine triphosphate and a suitable peptide substrate such as malantide (Malencik et al., 1983, Anal.
Biochem., 132, 34-40). The reaction was terminated by the addition of hydrochloric acid and the 32 p]-phosphopeptide quantified by spotting the reaction mixture onto phosphocellulose papers. The concentration of compound required to give 10% phosphotransferase activation is given as the EC 10 The compounds of Examples 1 to 27 had
EC
10 values in the range 0.09 100 pM.
Inhibition of Platelet Aggregation Human platelet-rich-plasma was separated from freshly drawn blood (in acid/citrate/dextrose) and treated with 100 JIM acetylsalicylic acid for 15 minutes at 37 0 C. A washed platelet suspension was then prepared in a Hepesisotonic saline buffer after a single centrifugation step and adjusted to a concentration of 1.5x10 8 cells/ml. Aliquots of this suspension were pre-incubated with compounds for minutes at 37 0 C, then challenged with 1.0 gM U46619. The extent of aggregation after 2 minutes were expressed as a percentage of control and results obtained are expressed as an IC 50 (concentration to cause 50% inhibition of platelet aggregation, The compounds of Examples 1 to 6, 9, 13, 15, 16, 18 to 21 and 23 to 26 had IC 50 values in the range 2 to 300 pM.
I I -I WO 93/07137 PCT/GB92/01847 32 Inhibition of Spontaneous Contraction in Guinea-Pig Colon Segments of isolated guinea-pig colon (2 cm) were suspended under 2 g tension in standard organ baths containing Krebs solution. The tissues were connected at the free end to isometric transducers which allow recording and display of developed tension on chart recorders. Online computer capture and analysis was used to quantify the effects of test compounds on spontaneous contractions.
io Inhibitory responses were calculated as maximum inhibition of spontaneous contraction distance over 3 consecutive pre and post dose 2 minute readings. The concentration of compound which caused 50% inhibition of the spontaneous contraction is given as the EC 50 The compounds of Examples 1 and 4 had EC 50 values of 21 and 60 ;M respectively.
Bronchodilatation In vitro Spiral strips of guinea-pig trachea were suspended in standard organ baths containing Krebs solution. The tissues were connected at the free end to isometric transducers which allow recording and display of developed tension on chart recorders. Tension was allowed to develop spontaneously and concentrations of test compounds added in a cumulative fashion. The concentration of compound which caused inhibition of the spontaneously developed tension is given as the IC 5 0 (pM) The -ompounds of Examples 1, 4, 5, 13, 18 and 20 to 22 had IC 50 values in the range 9 to 100 pM.
Measurement of cardiac muscle relaxation time in rabbit ventricle Papillary muscles from the right ventricle of female Albino New Zealand rabbits are mounted in standard organ i: WO 93/07137 PCT/GB92/01847 33 baths containing oxygenated Krebs solution. One end of the muscle is connected to an isometric transducer which allows recording of contractile force and its first derivative on chart recorders. Test compounds are added to the bath in a cumulative manner. Relaxation time is calculated as the time taken from peak tension to the end of the contraction.
Compounds which cause a decrease in the relaxation time indicate a positive lusitropic effect of use in the treatment of cardiovascular diseases where there is a component of diastolic failure such as congestive heart failure, angina, hypertension and cardiomyopathy.
WO 93/07137 PCT/GB92/01847 34 Example 1 6-Methyl-5-(2-naphthylthio)-3-(5-tetrazolyl)pyridin-2(1H)-one A mixture of chloroacetone 2-naphthalenethiol (16g) and potassium carbonate (13.8g) was stirred in dimethylformamide (100ml) at room temperature for 48 hours.
After diluting with ethyl acetate (400ml), the organic phase was washed with water (6x200ml), dried (MgSO 4 filtered and solvent removed at reduced pressure to give 1-(2-naphthylthio)propan-2-one (20.2g) as an oil. 1H NMR 5(CDC1 3 2.26(s,3H), 3.74(s,2H), 7.23-7.48(m,3H) and 7.71-7.93(m,4H).
1-(2-Naphthylthio)propan-2-one (16.2g) was dissolved in dimethylformamide (100ml) containing dimethylformamide dimethylacetal (9.52g) and boiled for 72 hours. The solution was cooled to room temperature, cyanoacetamide (6.72g) and sodium methoxide (8.64g) added, the solution boiled for a further 1 hour, poured into 10% aqueous acetic acid (300ml) and the precipitated product collected by filtration.
Recrystallisation from ethanol gave 3-cyano-6-methyl-5-(2naphthylthio)pyridin-2(1H)-one (8.24g) m.p. 247-249 0
C.
A mixture of 3-cyano-6-methyl-5-(2-naphthylthio)pyridin-2(1H)-one (1.0g) ammonium chloride (0.24g) and sodium azide (0.29g) in N-methylpyrrolidinone was heated at 140 0
C
for 4 hours. The reaction mixture was poured into 10% aqueous L acetic acid (50ml) and the precipitated product collected by filtration. Recrystallisation from dimethylformamide gave the title compound (0.53g) m.p.296-297 0
C.
WO093/07137 PCr/GB92/01847 Example 2 3- (l-Carboxymethyl-5-tetrazolyl) -6-methyl-5- (2-naphthylthio) pyridin-2 (lE) -one A mixture of 6-methyl-5-(2-naphthylthio)-3-(5tetrazolyl)pyridin-2 (lH)-one (6.37g), ethyl bromoacetate (3.16g) and sodium bicarbonate (1.74g) were stirred in dimethylformamide (7Oml) at room temperature for 10 hrs and at 50 0 C for 2 hours. The mixture was diluted with ethyl acetate (300m1) washel with water (6x200ml), dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, ethyl acetate eluant) to give in order of elution i) 3-(1-carboethoxymethyl-5tetrazolyl) -6-methyl-5- (2-naphthylthio) pyridin-2 (lH) -one (0 .54g) ii) 3- (2-carboethoxymethyl-5-tetrazolyl) (2-naphthylthio) pyridin-2 (lH) -one A solution of 3-(l-carboethoxymethyl-5-tetrazolyl)-6methyl-5-(2-naphthylthio)pyridin-2 (lH)-one (0.54g) in 1N sodium hydroxide/ethanol (40ml1:2.) was stirred at room temperature for 4 hours, poured into 2N hydrochloric acid (50m1) and extracted with ethyl acetate (3x50m1) The combined organic extracts were washed with water, dried (MgSO4) and solvent removed. The residue was recrystallised from ethanol to give the title compound (0.2g) m.p.
270 0 C(decomp) 1 H NMR 8(DMSO-d 6 2.47(s,3H), 5.50(s,2H), 7.33(dd,1H7.41-7.56(m,2H), 7.65(s,lH) 7.80-7.93(m,3H) and Examiple 3 n-Propyl- [5-(2-naphthylthio) -2-oxo-1, 2-dihydro-3-pyridyl] sodium salt A mixture of 5-bromopyridin-2(lH)-one (1.74g), 2naphthalenethiol (1.6g) and potassium carbonate (1.38g) were
II~CC;
WO 93/07137 PCT/GB92/01847 36 combined in dimethylformamide and heated to 130 0 C for 3 hours. The green solution was poured into 2N hydrochloric acid (80ml), ethyl acetate (50ml) and hexane (50ml) added and the mixture stirred for 1 hour. The precipitated solid was separated by filtration, and column chromatographed (silica, ethanol/dichloromethane) to give 5-(2naphthylthio)pyridin2(1H)-one (0.95g). 1H NMR (DMSO-d 6 6.41(d,1H), 7.33(dd,H), 7.42-7.53(m,3H), 7.64(s,H) and 7.76-7.90(m,4H) To a suspension of 5-(2-naphthylthio)pyridin- 2(1H)-one (0.9g) in tetrahydrofuran (5ml) cooled to -78 0
C
lithium diisopropylamide (1.5M in cyclohexane, 2.7ml) was added over 2 minutes. The mixture was stirred at -780C for minutes and at 0 0 C for 30 minutes, recooled to -78 0 C and din-propylphosphorochloridate (0.8g) added. After stirring for a further 15 minutes at -78 0 C and at 0 0 C for 30 minutes the solution was recooled to -78 0 C and, lithium diisopropylamide in cyclohexane, 2.7ml) was again added. The solution was stirred for 30 minutes at -78 0 C and at 0 0 C for minutes, quenched with 2N hydrochloric acid, diluted with ethyl acetate (50ml) and the organic phase washed with water (2x30ml), dried (MgSO4), filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica, dichloromethane-10% ethanol/dichloromethane) to give di-n-propyl 15-(2-naphthylthio)-2-oxo-1,2-dihydro-3pyridyl]phosphonate (0.41g). 1 H NMR (DMSO-d 6 0.82(t,6H), 1.47-1.62(m,4H), 3.88-3.97 7.33(dd,H), 7.44- 7.53(m,2H), 7.66(s,H), 7.74-7.90(m,4H) and 8.07(s,1H).
A solution of di-n-propyl [5-(2-naphthylthio)-2-oxo- 1,2-dihydro-3-pyridyl]phosphonate (0.37g) in a mixture of npropanol (3ml) and 2N sodium hydroxide (3ml) was boiled for hours. The solution was stood at room temperature overnight, the precipitated product was separated by filtration and recrystallised from ethanol to give the title compound (0.14g) m.p. >3000C. 1 H NMR (0.41g) 5(DMSO-d 6 4 WO 93/07137 7-PCT/GB92/01 847 0.64 3H) 1.31-1.42 2H) 3.46-3.60 2H), 7.19 1H), 7.33-7.81(m,61) and 7.93(s,1H).
Example 4 6-Mthyl-5-phenylthio-3- (5-tetrazolyl)pyridin-2 (iN)-one.
A mixture of chloroacetone (19.9m1) thiophenol (25.6m1) and potassium carbonate (34.5g) was stirred in dimethylforinamide (200m1) at room temperature for 48 hours. After diluting with ethyl acetate (BO0mi) the organic phase was washed with water (6x500m1) dried (MgSO4) and solvent removed at reduced pressure to give 1-phenylthiopropan-2-one (36.6g) I as an oil. 1 H NMR S(CDCl 3 2.26(s,3H), 3.65(s,2H) and 7.17- 15 7.47(m,5H).
Prepared in a similar way from the appropriate thiol or phenol and the 2-haloketone were the following:- 1-(4-chlorophenyl)propan-2-one: oil, yield 93%, 1 H NMR 8(CDCl 3 2.27(s,3H), 3.65(s,2H) and 7.17-7.28(in,4H); 1-(3-chlorophenylthio)propan-2-one:- oil, yield 74%, 1 H NMR 8(d 6 -DMSO) 2.23(s,31), 4.12(s,2H) and 7.20-7.36(m,4H); 1-(2-chlorophenylthio)propan-2-one:- oil, yield 85%, 1 H NMR 8(d 6 -DMSO) 2.26(s,3H), 4.14(s,2H), 7.15-7.31(m,3H) and 7. 4 5 (dd, 1H); 1-(3,4-dichlorophenylthio)propan-2-one:- oil, yield 85%, 1
H
NMR 8(d 6 -DMSO) 2.30(s,3H), 4.16(s,2i), 7.26(dd,1H) and 7.52- 7.56(m,2H); 2-(2-naphthyloxy)acetophenone:- oil, yield 88%, 1Hi NM?. 8(d 6 DMSO) 5.71(s,2H), 7.23-7.88(m,lOH), and 8.06-8.10(m,2H); WO 93/07137 WO 9307137PCr/GB92/01847 38 2-phenylthioacetophenone:- oil, yield 96%, 1 H NMR 6(CDCl 3 4.39(s,2H), 7.25-7.63(m,61), 7.85-8.02(m,5H) and 8.42(s,1H); and 2-(2-naphthylthio)acetophenone:- oil, yield 80%, 1 H NMR 8(CDCl 3 4.32(s,2H), 7.36-7.97(m,l2H).
1-Phenylthiopropan-2-one (36.6g) was dissolved in dimethylformamide (200m1) containing dimethylformamide dimethylacetal (31.9g) and boiled for 36 hours. The solution was cooled, cyanoacetamide (18.5g) and sodium methoxide (23.8) added, the mixture boiled for a further 2 hours, poured into water (800m1) containing acetic acid (80m1) and the precipitated product collected by filtration. The product was recrystallised from ethanol to give 3-cyano-6-methyl-5phenylthiopyridin-2(1H)-one (19.8g) m.p. 252-2541C.
A mixture of 3-cyano-6-methyl-5-phenylthiopyridin- 2(lH)-one (1,,21g) ammonium chloride (0.8g) and sodium azide (0.98g) in N-methylpyrrolidinone was heated at 130 0 C for 4 hours. Addition to water (200m1) containing acetic acid (3m1) precipitated the product which was recrystallised from ethanol to give the title compound (0.47g) m.p.
300 0 C(decomp).
Example (4-chlorophenylthio) -6-methyl-3- (5-tetrazolyl) pyridin- 2 (lH)-one 5- (4-Chlorophenyl) -3-cyano-6-methylpyridin-2 (lH) -one (21.6g) m.p. 305 0 C(decomp) was prepared from 1-(4-chlorothiophenyl)propan-2-one according to the method of Example 1 H NMR 8(DMSO-d 6 2.37(s,3H), 7.17(d,2H), 7.36(d,2H) and 8.26 (s,l1H) 1 35 -4 WO 93/07137 PCT/GB92/01847 39- From 5- (4-chlorophenylthio) -3-cyano-6-methylpyridin- 2(lH)-one (5.53g) the title compound (2.49g) m.p. 280 0
C
(decomp) was prepared according to the method of Example 1 H NMR B(DMSO-d 6 2.44(s,3H), 7.20(d,2H), 7.37(d,2H) and 8.34 (s,l1H).
Example 6 E-6- (2-Phenylethenyl) -5-phenylthio-3- 2(lE)-one A mixture of 3-cyano-6-methyl-5-phenylthio-pyridin- 2(1H)-one (0.55g), benzaldehyde (0.23g) and tetrabutylammonium fluoride (5m1, 1M in tetrahydrofuran) were boiled together for 6 hours, 4A molecular sieves (1g) were then added and heating continued for a further 50 hours. The reaction mixture was acidified with 2N hydrochloric acid (20m1) and the precipitated product separated by filtration washed with ethanol(30m1) and with diethyl ether (20 ml).
The dried product (0.7g) was added to a mixture of acetic anhydride (8m1) acetic acid (4m1) and sodium acetate (100mg) and boiled for 7 hours. On cooling the yellow product precipitated which was separated by filtration and washed with water (30m1) to give E-3-cyano-6- (2phenylethenyl)pyridin-2(lH)-one (0.56g). 1 H NMR 8(DMSO-d 6 7.16-7.56(m,1lH), 7.84(d,1H) and 8.31(s,1H).
From E-3-cyano-6- (2-phenylethenyl)pyridin-2 -one (0.25g), the title compound (0.05 g) m-p. 292 0 C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 1 H NMR B(DMSO-d 6 7.18-7.61(m,11H), 7.88(d,1H) and 8.38(s,1H).
WO 93/07137 PCT/GB92/01847 40 Example 7 3-Carboxymethyl-6-methyl-5-(phenylthio)pyridin-2(1H)-one 3-Cyano-6-methyl-5-phenylthiopyridin-2(1H)-one (5g) was suspended in tetrahydrofuran (20ml) and cooled to -78 0 C under nitrogen. Methyl lithium (32ml, 1.5M in diethyl ether) was added over 10 minutes, the mixture stirred for a further minutes at -78 0 C and for 4 hours at 0°C. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (10ml) followed by the addition of 2N hydrochloric acid. After stirring overnight at room temperature the precipitated product was collected by filtration, washed with water (50ml) and recrystallised from ethanol to give 3acetyl-6-methyl-5-phenylthiopyridin-2(1H)-one (1.39g), m.p.203 0
C.
A mixture of 3-acetyl-6-methyl-5-phenylthiopyridin- 2(1H)-one (1.39g), sulphur (0.26g) and morpholine (0.7g) was boiled for 2.5 hours. Sodium hydroxide (2N, 50ml) was added and boiling continued for a further 4 hours. After cooling to room temperature, the reaction mixture was filtered, the filtrate adjusted to pH 4 with conc. hydrochloric acid and the product separated by filtration to give the title compound (0.13g) m.p.217 0 C (decomp) after recrystallisation from ethanol. 1 H NMR 5(DMSO-d 6 2.31(s,3H), 7.04-7.18(m,3H), 7.30(t,2H) and 7.41(s,1H).
Example 8 6-Phenyl-5-phenylthio-3-(5-tetrazolyl)pyridin-2 (H)-one From 2-phenylthioacetophenone (11.4g), 3-cyano-6phenyl-5-phenylthiopyridin-2(1H)-one (7.76g) m.p. 212-2130C after recrystallisation from ethanol, was prepared according to the method of Example 4 WO 93/07137 PCr/GB92/01847 41 From 3-cyano-6-phenyl-5-phenylthiopyridin-2 (lH) -one (1.22g), the title compound (0.3g) m.p. 276-2781C after recrystallisation from ethanol, was prepared according to the method of Example 4 (c) Example 9 (3-Chlorophenylthio) -6-methyl-3- (5-tetrazolyl) pyridin- 2 (lH) -one From 1-(3-chlorophenylthio)propan-2-one (3.06g), 5-(3chlorophenylthio) -3-cyano-6-methylpyridin-2 (lH) -one 6g) m.p. 245 0 C after recrystallisation from ethanol, was prepared according to the method of Example 4 From 5- (3-chlorophenylthio) -3-cyano-6-methylpyridin- 2(1H)-one (1g) the title compound (1.O1g) m.p.277 0 C after recrystallisation from n-butanol, was prepared according to the method of Example 4 1 H NMR 8 (d 6 -DMSO) 2. 4 4(s, 3H) 7.11(d,lH) 7.25(m,2H), 7.33(t,l-) and 8.36(s,1H).
Example (2-Chlorophenylthio) -6-methyl-3- (5-tetrazolyl) pyridin- 2(lH)-one From l-(2-chlorophenylthio)propan-2-one (3.06g), 5-(2chlorophenylthio) -3-cyano-6-methylpyridin-2 (lH) -one 19g) m.p. 270 0 C after recrystallisation from ethanol was prepared according to the method of Example 4(b).
From 5- (2-chlorophenylthio) -3-cyano-6-methylpyridin- 2(lH)-one the title compound (0.94g) m.p.289 0 C after recrystallisation from n-butanol was prepared according to the method of Example 4 WO 93/07137 PCF/GB92/01847 -42 Example 11 4-Dichlorophenylthio) -6-methyl-3- 2(1H)-one.
From 1-(3,4-Dichlorophenylthio)propan-2-one (3.14g), 3- 4-dichlorophenylthio) -6-methylpyridin-2 (lH) -one (1.53g) m.p. 25500 after recrystallisation from ethanol, was prepared according to the method of Example 4 From 3-cyano-5-(3, 4-dichlorophenylthio) -6methylpyridin-2 (lH)-one, (0.75g), the title compound (0.75g) m.p.297 0 C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 4 1 H NMR and 8. 36 (s,1H).
Example 12 5-n-Butylthio-6-methyl-3- (5-tetrazolyl)pyridin-2 (iN)-one To a suspension of 3-cyano-6-methylpyridin-2(lH)-one (6.7g) in dimethylformamide (50m1), N-bromosuccinimide (8.85g) was added in portions over 10 minutes. The resulting mixture was stirred for 48 hours at room temperature, poured into water (iS0mi) and the precipitated material collected by filtration. The residue obtained was washed thoroughly with water and dried to give 5-bromo-3-cyano-6-methylpyridin- 2 (1H) -one (8.88g) m.p. 254-255'C (decomp) 1H NMR 8 (d6 DMSQ) 2.35 3H) and 8.35 (s,l1H).
A mixtu:edof -rm--yn--ehlyin2(Hoe (2.13g) and bis(butylthio)copper was heated in quinoline (l0ml) and pyridine (3m1) at 1900C for 6 hours. The mixture Teprecipitated solid was collected by filtration and column chromatographed (silica gel, dichloromethane WO 93/07137 PCT/GB92/01847 43 ethanol/dichloromethane) to give 5-butylthio-3-cyano-6methylpyridin-2(1H)-one (0.12g) m.p. 206-208 0 C after recrystallisation from ethanol.
From 5-butylthio-3-cyano-6-methylpyridin-2 (1H) -one (0.llg) the title compound (0.07g) m.p. 258-259 0 C after recrystallisation from ethanol, was prepared according to the method of Example 4(c).
Example 13 5-n-Butylthio-6-(4-methoxy-3-propoxyphenyl)-3-(5tetrazolyl)pyridin-2(1H)-one A mixture of 3'-hydroxy-4'-methoxyacetophenone (A.
Brosei, H. Gurien, A. I. Rachlin and S. Teitel, J. Org.
Chem., 1967, 32, 1269) (8.31g), iodopropane (17g) and potassium carbonate (9.91g) in acetone (50ml) was boiled for 18 hours. The mixture was cooled to room temperature diluted with ethyl acetate (200ml) and washed with water (200ml), 2N sodium hydroxide (2 x 200ml) and water (2 x 200ml). The organic phase was dried (MgS04), and solvent removed at reduced pressure to give 4'-methoxy-3'-propoxyacetophenone (10.3g) as an oil that solidified on standing m.p. 63-64 0
C.
Copper (II) bromide (13.4g) and 4'-methoxy-3'propoxyacetophenone (6.25g) were combined in ethyl acetate and chloroform (30ml) and the mixture boiled for minutes. The reaction mixture was cooled to room temperature, filtered and the residue washed thoroughly with dichloromethane. The combined organic phase was washed with aqueous ammonia (3x50ml) and water (2x50ml), dried (MgS04) and solvent removed at reduced pressure to give 2bromo-4'-methoxy-3'-propoxyacetophenone (4.94g) m.p. 76-77 0
C
after recrystallisation from aqueous ethanol.
SI II WO 93/07137 PCI'/G B92/01 847 -44 From 2-bromo-4 'methoxy-3 '-propoxyacetophenone (4 .3g), 2-n-butylthio-4 '-methoxy-3 '-propoxyacetophenone 17g) m.p.
53-54'C after recrystallisation from ethanol was prepared according to the method of Example 4 From 2-n-butylthio-4 -methoxy-3 '-propoxyacetophenone (2 .52g), 5-n-butylthio-3-cyano-6- (4-methoxy-3-propoxyphenyl) pyridin-2 (1H)-one (2.96g) m.p.137-138 0 C after recrystallisation from ethanol, was prepared according to the method of Example 4 From 5-n-butylthio-3-cyano-6- (4-methoxy-3propoxyphenyl) pyridin-2 (lH) -one the title compound (0.93g) m.p.189-190 0 C after recrystallisation from ethanol was prepared according to the method of Example 4 Example 14 5-Benzyl-6-phenyl-3- (5-tetrazolyl) pyridin-2 (lE) -one From 3-phenylpropiophenone (4.21g), methylphenyl-6-phenylpyridin-2 (lH)-one (2.15g) m.p. 305*C (decomp) after recrystallisation from ethanol, was prepared according to the method of Example 1 H NMR 8(CDCl 3 3.8O(s,2H), 7.02(dd,2H), 7.20-7.39(m,3H), 7.40-7.60(m,5H) and 7.7l(s,lH).
From 3-cyano-5-methylphenyl-6-phenylpyridin-2 (1H) -one IT 86g) the title compound 64g) m. p. 2 6 9C (decomp) af ter recrystallisation from ethanol, was prepared according to the method of Example 4 1H~ NMR 8 (d 6 -DMSO) 3. 7 8(s, 2H) 7.05(d,2H), 7.18-7.30(m,3H), 7.51(m,5H) and 8.28(s,l1) WO 93/07137 PCT/GB92/01847 Example (2-naphthyloxy) -6-phenyl-3- (5-tetrazolyl)pyridin-2 (12)-one F~rom 2-(2-naphthyloxy)acetophenone (2.62g), (2-naphthyloxy)-6-phenylpyridin-2(1H)-one (2.23g) m.p. 272"C (decomp) after recrystallisation from ethanol was prepared according to the method of Example 1 H NMR 8(d 6
-DMSO)
7.28(dd,1H), 7.39-7.92(m,11H) and 8.31(s,1H).
From 3-cyano-5-(2-naphthyloxy)-6-phenylpyridin-2 (iN)one (1g) the title compound (0.93g) m.p.307 0 C (decomp) after recrystallisation from n-butanol, was prepared according to the method of Example 4 1 H NMR 8 (d 6 -DMSO) (7.31 (dd, 1H) 7.37-7.92(m,11H) and 8.28 1H).
Example 16 6- (2-Naphthyl) -5-phenylthio-3- (5-tetrazolyl) pyridin-2 (12)-one From 2-(2-phenylthio)acetonaphthone (13g), 3-cyano-6- (2-naphthyl)-5-phenylthiopyridin-2 (11-)-one (4.9g) m.p.228 0
C
after recrystallisation from n-butanol, was prepared according to the method of Example 4 From 3-cyano-6- (2-naphthyl) -5-phenylthiopyridin-2 (lH) one (1.82g), the title compound (1.73g) m.p. 249-250'C after recrystallisation from n-butanol, was prepared according to the method of Example 4 Example 17 (2-Naphthylthio) -6-phenyl-3- (5-tetrazolyl)pyridin-2 (12)-one From 2-(2-naphthylthio)acetophenone 3-cyano-5-(2naphthylthio)-E-phenylpyridin-2(1H)-one (3.4g) m.p.256-258 0
C
WO 93/07137 PCT/GB92/01847 46 after trituration with water/ethyl acetate, according to the method of Example 4(b) From 3-cyano-5-(2-naphthylthio)-6-phenylpyridin-2(1H)one the title compound (2.7g) m.p.272-274 0 C after recrystallisation from dimethylformamide/ethanol, was prepared according to the method of Example 4(c) Example 18 5-n-Butylthio-6-(3,4-dimethoxyphenyl)-3-(5-tetrazolyl)pyridin-2 (1H) -one) From 2-bromo-3',4 '-dimnethoxyacetophenone (3.89g) 2-nbutylthio-3',4 -dimethoxyacetonphenone (3.87g) isolated as an oil was prepared according to the method of Example 4(a) 1H NMR 8(CDCl 3 O.90(t,3H), l.31-l.63(m,4H), 2.58(t,2H), 3.75(s,2H), 3.94(s,3H), 3.95(s,3H), 6.89(d,1H), 7.55(d,lH) and 7.60(dd,lH) From 2-n-butylthio-3',4'-dimethoxyacetophenone (3.87g), 5-n-butylthio-3-cyano-6-(3,4-dimethoxyphenyl)pyridin-2(lH)one (1.4g) m.p.192-193 0 C after recrystallisation from ethanol was prepared according to the method of Example 4(b) From 5-n-butylthio-3-cyano-6-(3,4-dimethoxyphenyl)pyridin-2(lH)-one (1.03g), the title compound ((0.84g) m.p.197-198 0 C after recrystallisation from ethanol was prepared according to the method of Example 4(c) Example 19 3- 6-Methyl-5-(2-naphthylthio)-2-oxo-1, 2-dihydro-3-pyridyl]propionic acid To a suspension of 3-cyano-6-methyl-5-(2-naphthythio)pyridi' 2(lH)-one (2.64g) in dichioromethane (50m1) at -78 0
C
WO 93/07137 PCT/GB92/01847 47 a solution of diisobutylaluminium hydride (9.lml, 1M in dichloromethane) was added over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 24 hours. Additional diisobutylaluminium hydride (14ml, 1M in dichloromethane) was added and stirring continued for 24 hours. After cooling to 0 0 C the mixture was quenched with 2N hydrochloric acid (50ml)and stirred for 3 hours. The organic phase was separated and the aqueous phase extracted with dichloromethane (3x50ml). The combined organic extracts were washed with saturated sodium hydrogen carbonate (50ml), water (3x50ml), dried (Na 2
SO
4 filtered and solvent removed at reduced pressure. The residue (1.08g), and carboethoxymethylene triphenylphosphorane(1.52g) were heated together at reflux in toluene (16ml) for 3 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and washed with water (2x50ml), dried (Na 2 SO4), filtered and solvent removed at reduced pressure to give after column chromatography (silica gel, 20% ethyl acetate/hexane eluant) ethyl E-3-[6-methyl-5-(2-naphthylthio)-2-oxo-1,2-dihydro-3pyridyl]propenoic acid (1.06g) m.p.206 0 C. 1H NMR 8(CDC13) 1.28(t,3H), 2.60(s,3H), 4.21(q,2H), 7.06(d,1H), 7.24(dd,1H), 7.41-7.51(m,3H), 7.55(d,1H) and 7.68-7.81(m,4H).
Ethyl E-3-[6-methyl-5-(2-naphthylthio)-2-oxo-1,2dihydro-3-pyridyllpropenoate (0.9g) and tris(triphenylphosphine)rhodium chloride (0.23g) were stirred in ethanol (40ml) under 1 atmosphere of hydrogen for 16 hours.
Solvent was removed at reduced pressure, the residue 2 dissolved in ethyl acetate (100ml) and washed with 2N hydrochloric acid (50ml), saturated sodium hydrogen carbonate and water (2x50ml). The organic phase was dried (Na 2
SO
4 filtered and solvent removed at reduced pressure to give ethyl 3-[6-methyl-5-(2-naphthylthio)-2-oxo-1,2-dihydro- 3-pyridyl]propanoate (0.82g). 1 H NMR 8(CDC13) 1.14(t,3H), 2.58-2.73(m,2H), 2.74-2.89(m,2H), 4.05(q,2H), 7.22(dd,1H), 7.32-7.81(m,7H) and 12.58(br.s).
WO 93/07137 PCT/GB92/01847 -48 A solution of ethyl 3-[6-methyl-5-(2-naphthylthio)-2oxo-1, 2-dihydro-3-pyridyllpropanoate 6g) in 2N sodium hydroxide/ethanol 20m1) was stirred at room temperature overnight. Solvent was removed at reduced pressure, the residue dissolved in 1N sodium hydroxide (60m1), washed with dichloromethane (2x50m1) The aqueous phase was cooled (ice bath) and acidified with 2N hydrochloric acid. The precipitate was collected by filtration washed thoroughly with water and recrystallised from ethyl acetate to give the title compound (0.48g) m.p.182 0
C.
Example 5-Phenylthio-6- (4-methoxy-3-propoxyphenyl) (5-tetrazolyl) pyridin-2 (iN)-one a) From 2-bromo-4 '-methoxy-3 '-propoxyacetophenone 87g), 2-phenylthio-4 '-methoxy-3 '-propoxyacetophenone (3.11g) isolated as an oil, was prepared according to the method of Example 1 H NMR B(CDC1 3 l.04(t,3H), l.80-l.94(m,2H), 3.93(s,3H)3.99(t,2H), 4.24(s,2H), 6.87(d,lH) and 7.20- 7.57(m,7H).
b) From 2-phenylthio-4 '-methoxy-3 '-propoxyacetophenone Olg) 3-cyano-5-phenylthio-6- (4-methoxy-3propoxyphenyl)pyridin-2 (1H) -one (1.98g) m.p.210-211' after recrystallisation from ethanol, was prepared according to the method of Example 4 (b) C) From 3-cyano-5-phenylthio-6-(4-methoxy-3propoxyphenyl)pyridin-2 (1H) -one (0 .71g), the title compound (0.69g) m.p.191-192' after recrystallisation from ethanol, II was prepared according to the method of Example 4 494 Example 21 5-Methylthio-6- (4-methoxy-3-propoxyphelyl) (5-tetrazolyl) pyridin-2 (lE) -one Potassium thioacetate (5.02g) was added to a cooled (ice bath) solution of 2-bromo-4'-methoxy-3'-propoxyacetophenone (6.3g) in dimethylformamide (120m1) containing 4A molecular sieves (7g) The mixture was warmed to room temperature and stirred for 18 hours. After diluting with diethyl ether (200ml)the organic phase was washed with 1N hydrochloric acid (200m1), water (4xJ.OOml), dried (MgSO 4 and solvent removed at reduced pressure to give 2-acetylthio-41methoxy-3'-propoxyacetophenone (6.09g) 1 H NMR B(CDCl 3 1.05(t,3H), l.79-l.94(m,2H), 2.40(s,3H), 3.94(s,3H), 4.O6(t,2H), 4.36(s,2H), 6.90(d,1H), 7.52(d,lH) and 7. 63 (dd, 1Hi) To a solution of 2-acetylthio--4'-methoxy- 31 -propoxyacetophenone (1.12g) in methanol (15m1), a solution of sodium methoxide (0.22g) in methanol (7m1) was added. The solution was stirred for one hour and then treated with iodomethane (0.56g) in methanol(l0ml). The solution was stirred for a further 18 hours to give after removal of solvent 2methylthio-4'-methoxy-3'-propoxyacetophenone (0.51g) 1H NMR B(CDCl 3 1.05(t,3H), 1.81-2.08(m,2H), 2.16(s,3H-), 3.73(s,2H), 3.94(s,3H), 4.04(t,2H), 6.89(d,lH) and 7.55-7.61(m,2H).
142((C) From 2-methylthio-4 '-methoxy-3 '-propoxyacetophenone (0 .51g), 3-cyano-5-methylthio-6-(4-methoxy-3-propoxyphenYl) pyridin-2(1H)-one (0.19g) m.p.212-213 0 after recrystallisation from ethanol, was prepared according to the method of Example 4 From 3-cyano-5-methylthio-6-(4methoxy- 3 -propoxy phenyl)pyridin-2(lH)-one (0.17g), the title compound (0.10g) -WIIfr LAA t I i ,kd. )JU n LWWJYA J. 'I.LVJ U %LLvJvu6) WO 93/07137 PCI'/GB92/01847 m.p.225-226 0 after recrystallisation from ethanol, was prepared according to the method of Example 4(c).
Example 22 5-Ethylthio-6- (4-methoxy-3-propoxypheflyl) (5-tetrazolyl) pyridin-2 (iN)-one a) From 2-acetylthio-4-'methoxy-3 L-propoxyacetophenone (1 .12g), 2-ethylthio-4 '-methoxy-3 '-propoxyacetophenone (0.54g) was prepared according to the method of Example 21(b). 1 H NMR 8(CDCl 3 1.05(t,3H), l.27(t,3H), 1.87- 1.99(m,2H), 2.57-2.69(m,2H), 3.76(s,2H), 3.93(s,3H), 4.04(t,2H), 6.89(d,1H) and 7.54-7.62(m,2H).
From 2-ethylthio-4 '-methoxy-3 '-propoxyacetophenone (0 .54g), 3-cyano-5-ethylthio-6- (4-methoxy-3-propoxyphenyl) pyridin-2(1H)-one (0.18g) m.p.186-187 0 after trituration with ethanol, was prepared according to the method of Example 4(b).
From 3-cyano-5-ethylthio-6- (4-methoxy-3-propoxyphenyl) pyridin-2(1H)-one (0.17g), the title compound (0.11g) m.p.223-224 0 after recrystallisation from ethanol, was prepared according to the method of Example 4 Example 23 5-Bromo-6- (4-methoxy-3-propoxyphenyl) (5-tetrazolyl) pyridin-2 (iN)-one A solution of 3-cyano-6-(4-methoxy-3-propoxyphenylpyridin-2(lH)-one (1.42g) and N-bromosuccinimide (0.89g) in dimethylformamide (20m1) was boiled for one hour and diluted with water (30 Oml). The precipitated 5-bromo-3-cyano-6- (4methoxy-3-propoxyphenyl)pyridin-2 (lH) -one (1 .73g) m.p.236- 2370 was washed with water and diethyl ether.
WO 93/07137 PCT/GB92/01 847 -51 From 5-bromo-6- (4-methoxy-3-propoxyphenyl) pyridin- 2(lH)-one (1.45g), the title compound (1.55g) m.p.238-239 0 after recrystallisation from dimethylformarnide/water, was prepared according to the method of Example 4 Example 24 6- 4-Dimethoxyphenyl) -5-pentyl-3- 2(lH)-one.
To a mixture of heptanoyl chloride (5.3g) and 1,2dimethoxybenzene (5g) in dichloromethane (50ml) aluminium trichloride (5g) was added portionwise. After the addition was complete the mixture was boiled for one hour, cooled to room temperature and poured into water. The dichloromethane was separated and the aqueous phase extracted with ethyl acetate (3x50m1) The combined organic phases were dried (MgS0 4 and solvent removed at reduced pressure to give 3',4'-dimethoxyheptanophenone (8.8g) m.p. 35-37 0
C.
From 3',4'-dimethoxyheptanophenone 3-cyano-6- 4-dimethoxyphenyl) -5-pentylpyridin-2 (lH) -one (0 .71.g) m.p.
182-184 0 C after recrystallisation from ethanol, was prepared I according to the method of Example 4 From 3-cyano-6- 4-dimethoxyphenyl) 2(lH)-one (0.71g), the title compound (0.6g) m.p. 212-214 0
C
after recrystallisation from ethanol, was prepared according to the method of Example 4 Example 6- (2-Naphthyl) -5-phenoxy-3- (5-tetrazolyl)pyridin-2 (iN)-one.
From 2-bromo-2'-acetonaphthone (2.25g), 2-phenoxy-2'-i acetonaphthone (2.2g) was prepared according to the method of WO 93/07137 PCU/GB92/01847 -52 Example 4 1 H NMR (CDCl 3 5. 3 9(s,2H), 6. 85- 7. 01(m,3H), 7.25-7.33(m,2H), 7.54-7.65(m,2H) 7.87-8.06(m,4H) and 8.54 (s,1H).
From 2-phenoxy-2'-acetonaphthofle 3-cyano-6-(2naphthyl)-5-phenoxypyridifl2 (lH)-one (0.73g) m.p. 253-2541C after recrystallisation from n-butanol was prepared according to the method of Example 4 From 3-cyano-6-(2-naphthyl)-5-phenoxypyridin-2(lH)-one the title compound (0.49g) m.p. 279 0 C (decomp) after recrystallisation from ethanol, was prepared according to the method o f Example 4 IH NMR 8 (d 6 -DMSO) 7.0l1-7. 0 4(m, 3H) 7.27-7.33(m,2H) 7.57-7.60(m,2H) 7.79(d,lH) 7.91- 7.98(m,3H), 8.23(s,1H) and 8.32(s,lH).
Example 26 5-n-Butylthio-6- (E-1-propenyl) -4-methoxyphenyl] tetrazolyl) pyridin-2 (iN)-one.
To a suspension of 3-cyano-6-[3-(E-1-prr-penyl)-4metho~yphenyllpyridin-2(lH)-one (PCT/GB9l/01663) (2g) in dimethylformamide (2Oml), N-iodosuccinimide (2g) was added and the mixture stirred in the dark for 24 hours. After diluting with ethyl acetate (10 Qml), washing with water (6x50m1), drying (MgSO 4 and removing solvent at reduced pressure 3-cyano-5-iodo-6- (E-l-propenyl) -4methoxyphenyllpyridin-2(lH)-ole (2.6g) m.p. 233-2341C (decomp) after recrystallisation from ethanol was obtained.
From 3-cyano-5-iodo-6- (E-1-propenyl) -4methoxyphenyllpyridifl 2 (1H) -one 3-cyano-5-butylthio-6- (E-1-propenyl) -4-methoxyphenyl)pyridin-2 -one (0 .065g) was prepared according to the method of Example 12 1 H NMR S(CDCl 3 0.79(t,3H), i.19-1.36(m,4H), 1.93(d,3H), 2.54(t,2H), WO 93/07137 PCr/GB92/01847 -53- 6.27-6.42 (in,1i), 6.71 6. 99 (in, 1Hi), 7 .4 9 (in, 1H), 7.67(s,1H) and 8.05(s,1H).
From 5-butylthio-3-cyano-6- (E-3-prop-l-enyl-4methoxyphenyl)pyridin-2(1H)-one (0.065g), the title compound (0.015g) m.p.225-2261C after recrystallisation from ethanol was prepared according to the method of Example 4 Example 27 Ethyl (5-phenylthio-2-oxo-1, 2-dihydro-3-pyridyl) phosphonate sodium salt.
Using phenyltributyltin sulphide (l0g) and bromopyridine (4 .32g), 2-methoxy-5-phenylthiopyridine 8g) was prepared according to the method of Kosugi et al (Bull.
Chem. Soc. Jpn., 1985, 58, 3657) 1HNMR 8(d 6
-DMSO)
3.89(s,3H), 6.91(d,1H), 7.16-7.35(m,5H), 7.80(dd,1H) and 8.30(d,H).
A mixture of 2-methoxy-5-phenylthiopyridine (1.74g), chlorotriinethylsilane (2.16g) and sodium iodide (3.0g) were stirred together in acetonitrile (10m1) overnight. The mixture was diluted with ethyl acetate (50m1) and washed with water (3x50m1), dried (MgSO 4 and solvent removed at reduced pressure. The residue was suspended in ethyl acetate (20m1) stirred for 20 minutes and filtered to give as the residue phenylthiopyridin-2(lH)-one (0.87g) m.p.181-1831C.
From 5-phenylthiopyridin-2(lH)-one (0.61g), diethyl phenylthio-2-oxo-1, 2-dihydro-3-pyridyl) phosphonate 21g) m.p.208-209 0 C after recrystallisation from ethanol, was prepared according to the method of Example 3 From diethyl (5-phenylthio-2-oxo-1,2-dihydro-3pyridyl)phosphonate(0.18g), the title compound (0.025g) m.p.
280 0 C (softens) after recrystallisation from ethanol/water, WO 93/07137 WO 9307137PCT/GB92/01847 -54 was prepared according to the method of Example 3 1H NMR 8(d 6 -DMSO) 1.03(t,3H), 3.60(m,2H), 6.98-7.30, 7.68(d,1H) and 7.87(s,lH).
Example 28 5-n-Butylthio-6- (4-methoxy-3-n-propylphenyl) tetrazolyl)pyridin-2 (1H)-one From methoxy-3'-n-propylacetophenone 2-bromo-4 '-methoxy-3'-n-propylacetophenone 4g) was prepared according to the method of Example 13(b) A-H NMR 8(CDCl3) 0.95(t,3H), 1.54-1.69(m,2H), 2.61(t,2H), 3.90(s,3H), 4.41(s,2H), 6.89(d,1H), 7.78(d,1H), 7.86(dd,1H).
fEape4a.~ M From 2-bromo-4 '-methoxy-3 '-n-propylacetophenone 4g), 2-n-butylthio-4 '-methoxy-3 '-n-propylacetophenone 6g) was prepared) acodn to e5mthodof Ex3amplem2H) 1.4(a).0m1H) 0.89(s,3H), 3.88(t,3H), 6.86(d14() H, .7d1H) and(mH 7.84 (dd,1H).
From 2-n-butylthio-4 '-methoxy-3 t-n-propylacetophenone (4 .6g) 5-n-butylthio-3-cyano-6- (4-methoxy-3-npropylphenyl)pyridin-2(lH)-one (0.73g) was prepared according to the method of Example 4 1 H NMR 8 (DMSO-d6) 0.73(t,3H), 0.93 31), 1.07-1.31 (in, 1.49-1.64 (in,2H) 3.84(3, 3H), 7.05(d,lH), 7.28(d,1H), 7.38(dd,1H) and 8.36(s,1H).
From 5-n-butylthio-3-cyano-6- (4-methoxy-3-npropylphenyl)pyridin-2(1H)-one the title compound (0.43g) in.p. 210-2121C, after recrystallisation from ethanol, was prepared according to the method of Example 4(c).
WO 93/07137 PCT/GB92/01 847 Example 29 5-n-Butylthio-6- (E-1-propenyl) -4-methoxyphenyl] tetrazolyl)pyridin-2 (lH) -one From 3-cyano-6- (E-1-propenyl) -4-methoxyphenyl] pyridin-2(1H)-one (WO 92/06085) 3-cyano-5-iodo-6-[3-(E- 1-propenyl)-4-methoxyphenyllpyridin-2 (lH)-one (2.6g) m.p.
233-234 0 C (decomp), after recrystallisation from ethanol, was prepared according to the method of Example 23(a) replacing N -bromosuccinimide with N-iodosuccinimide.
From 3-cyano-5-iodo-6- (E-2.-propenyl) -4methoxyphenyllpyridin-2 (1H) -one 5-n-butylthio-3-cyano- 6- (E-1-propenyl) -4-methoxyphenyllpyridin-2 (lH) -one (0.065g) was prepared according to the method of 12(b).
From 5-n-butylthio-3-cyano-6- (E-1-propenyl) -4methoxyphenyl~pyridin-2(1H)-one (0.065g), the title compound (0.66g) m.p. 225-226 0 C after recrystallisation from ethanol, was prepared according to the method of Example 4 chromatographed (silica gel, dichloromethane 4 I-'i WO 93/07137 PCT/GB92/01847 56 Example Pharmaceutical compositions for oral administration are prepared by combining the following w/w 6-methyl-5-(2-naphthylthio)-3- (5-tetrazolyl)pyridin-2(IH)-one 0.5 3.0 7.14 2% w/w Soya lecithin in soya bean oil 90.45 88.2 84.41 Hydrogenated vegetable shortening and beeswax 9.05 8.8 8.45 The formulations are then filled into individual capsules.
soft gelatin Example 31 A pharmaceutical composition for parenteral administration is prepared by dissolving the title compound of Example 2 (0.02 g) in polyethylene glycol 300 (25 ml) with heating. This solution is then diluted with water for injections Ph. Eur. (to 100 ml). The solution is then sterilised by filtration through a 0.22 micron membrane filter and sealed in sterile containers.
1_ I.lr~iii-- 56a Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
940822,p:\oper\dab,26933.spe,56
A

Claims (4)

1. A compound of the formula (1) a R R ON R1# 0 R Formula (1) or a pharmaceutically acceptable salt thereof, wherein RO is OH or a bioprecursor thereof, Rl is A 0 2 H, P(Z) (OH) (OR 2 SO 2 H, S0 3 H or optionally substituted in the 1-position by CH 2 CO 2 H or a bioprecursor thereof, AO is CH 2 CH 2 CH 2 CHF, CE' 2 CR 3 (0R 4 CO or C(OR 5 (OR 6 R 2 is phenyl, C 3 5 cycloalkyl, C 3 5 cycloalkyl Cl.. 4 alkyl, or C 1 8 alkyl optionally substituted by Cl 1 4 alkoxy, R 3 is H, methyl or ethyl, R 4 is H or Cl 1 3 alkyl, R 5 and R 6 are each C 1 3 alkyl or together form a 1,2- ethanediyl group or 1,3-propanediyl group, Z is 0 or S, Ra is halo or XlYl, .68 PCTIGB 92/ 018 47 58 -13 JANUARY 1994 Xl is CH 2 0 or S, Y 1 is C 1 6 alkyl or Ar, Ar is phenyl optionally substituted by one to three groups independently selected from halo, Cl 1 6 alkyl, C 2 6 alkenyl, G>. 6 alkoxy, Cl. 6 polyfluoroalkyl or Cl- 6 polyfluoroalkoxy, or Ar is 1-naphthyl or 2-naphthyl, R is H, Cl 1 6 alkyl or X 2 Arl wherein X 2 is a bond or ethenyl and Ar 1 is phenyl optionally substituted by one to three groups independently selected from Cl. 6 alkyl, C 2 6 alkenyl, Cl.. 6 alkoxy, C 3 6 alkenyloxy, C 2 6 cycloalkyl, C 2 6 cycloalkoxy, Cl 1 6alkylthio, phenyl, phenylthio, benzyloxy, Cl 1 6 polyfluoroalkyl, C 1 6 polyfluoroalkoxy, halo, N(R 7 2 or NHCOR 7 wherein R 7 is H or Cl. 6 alkyl, or -X(CH2)nY attached to adjacent carbon atoms of the phenyl ring wherein X and Y are I independently CH 2 or 0 and n is 1 to 3, wherein said C 1 6 alkyl, C 2 6 alkenyl or Cl. 6 alkoxy groups can be 11 independently substituted by OH, 6 alkoxy, C 2 6 cycloalkyl, N(R 7 2 C0 2 R 7 or CON(R 7 2 or Ar 1 is 1-naphthyl optionally substituted in the 4-position by hydroxy or Cl 1 6 alkoxy, 2-naphthyl optionally substituted in the 1-position by hydroxy or Cl.. 6 alkoxy, 3-phenanthryl, 9- phenanthryl, 2-quinolinyl, 4-quinolinyl, 3-thianaphthenyl or
2-benzofuranyl, with the proviso that R 1 is not an unsubstituted group when RO is OH, Ra is Clj 4 alkyl, and R is RbOR Rb~ United K'Mr:domn o-t uT~ficelSBTUE SHEET PCT Intermalional Application SUSTI 68 58a 4 alkyl substituted ithia, -NH 2 or wherein Rb is Cl 1 6 alkyl, C 3 6 alkenyl, or C 1 by 1 to 3 fluoro groups, and Rc is halo, C 1 4 alkyl, Clj 4 alkoxy, Clp 4 alky -NHCOR 7 2. A compound according to claim 1 wherein R is X 2 Arl. r Ot$ United Kingdom P.-2c-t Sfc SU S S U NTE SHEET .Pcr Internnticnal App~cation WO 93/07137 PCr/GB92/01847
59- 3. A compound according claim 1 or 2 wherein Rl is A 0 2 H or A 0 C0 2 R 9 in which R 9 is an ester-forming group. 4. A compound according to claim 1 or 2 wherein Rl is P(Z) (OH) (OR 2 or P(Z) (OR 2 2 A compound according to claim 2. or 2 wherein R 1 is S0 2 H, S0 3 H or 6. A compound according to any one of claims 1 to wherein Ra is XlYl. 7. A compound according to claim 1 which is 6-methyl-5- 2 -naphthylthio)-3-(5-tetrazolyl)pyridin-2 (18)- one, 3- (1-carboxymethyl-5-tetrazolyl) -6-methyl-5- (2-naphthylthio) pyridin-2 (18)-one, n-propyl- (2-naphthylthio) -2-oxo-1, 2-dihydro-3-pyridyl] phosphonate, 6-methyl-5-phenylthio-3- (5-tetrazolyl) pyridin-2 (18)-one, (4-chlorophenylthio) -6-methyl-3- (5-tetrazolyl) pyridin- 2 (1H) -one, E-6- (2-phenylethenyl) -5-phenylthio-3- (5-tetrazolyl) pyridin- 2(1H)-one, 3-carboxymethyl-6-methyl-5- (phenylthio) pyridin-2 (18)-one, 6-phenyl-5-ph,,nylthio-3- (5-tetrazolyl)pyridin-2 (18)-one, (3-chlorophenylthio) -6-methyl-3- 2 (1H) -one, WO 93/07137 PCT/GB92/01847 (2-chiorophenyithia) -6-methyl-3- (5-tetrazolyl) pyridin- 2(1H)-one, 4-dichlorophenylthio)-6-methyl-3-'(5-tetrazolyl)pyridin- 2(1H)-one, -n-butylthio-6-methyl-3- (5-tetrazolyl)pyridin-2 (18)-one, 5-n-butylthio-6-(4-rnethoxy-3-propoxyphenyl)-3- pyridin-2 (18)-one, 5-benzyl-6-phenyl-3-(5-tetrazolyl)pyridin-2 (18)-one, 5-(2-naphthyloxy)-6-phenyl-3-(5-tetrazolyl)pyridin-2 (18)-one, 6-(2-naphthyl)-5-phenylthio-3-(5-tetrazolyl)pyridin-2 (18)- one, 5-(2-naphthylthio)-6-phenyl-3- (5-tetrazolyl)pyridin-2 (18)- one, 5-n-butylthio-6- 4-dilnethoxyphenyl) (5-tetrazolyl) pyridin-2 (18)-one,
253- £6-methyl-5- (2-napthylthio) -2-oxo-1, 2-dilydro-3-pyridyl] propionic acid, 5-phenylthio-6- (4-methoxy-3-propoxyphenyl) (5-tetrazolyl) pyridin-2 (18)-one, 5-methylthio-6- (4-methoxy-3-propoxyphenyl) (5-tetrazolyl) pyridin-2 (18)-one, 5-ethylthio-6- (4-methoxy-3-propoxyphenyl) (5-tetrazolyl) pyridin-2 (iN)-one, WO 93/07137 PCT/GB92/01847 61 5-bromo-6-(4-methoxy-3-propoxyphenyl)-3-(5-tetrazolyl)- pyridin-2(1H)-one, 6-(3,4-dimethoxyphenyl)-5-pentyl-3-(5-tetrazolyl)pyridin- 2(1H)-one, 6-(2-naphthyl)-5-phenoxy-3-(5-tetrazolyl)pyridin-2(lH)-one, 5-n-butylthio-6-[3-(E-1-propenyl)-4-methoxyphenyl)-3-(5- tetrazolyl)pyridin-2(1H)-one, ethyl (5-phenylthio-2-oxo-1,2-dihydro-3-pyridyl)phosphonate, 5-n-butylthio-6-(4-methoxy-3-n-propylphenyl)-3-(5- tetrazolyl)pyridin-2(1H)-one, or 5-n-butylthio-6-[3-(E-1-propenyl)-4-methoxyphenyl]-3-(5- tetrazolyl)pyridin-2(1H)-one, or a pharmacertrically acceptable salt thereof. 8. A compound according to any one of claims 1 to 7 for use as a medicament. 9. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier. A process for preparing a compound of the formula as defined in claim 1 or a pharmaceutically acceptable salt thereof which process comprises a) for compounds wherein R 1 is A 0 CO 2 H or A 0 C0 2 R 9 and i) AO is CR 3 (OR 4 1 reacting in the presence of a strong base a compound of the formula (2) L i i WO 93/07137 PCT/GB92/01847 62 a R R ION OR Formula (2) wherein R 11 is methyl and R, and R a are as defined in claim 1, with a compound of the formula (3) R 3 COC02R 9 (3) wherein R 3 is as defined in claim 1 and R 9 is an ester- forming group to form a compound of the formula (4) a R R 12 O N R OR Formula (4) wherein R 1 2 is CR 3 (OH) C O 2 R 9 and R, R 3 R 9 R 1 1 and R a are as hereinbefore defined and thereafter optionally reacting with a C1- 3 alkylating agent to form the corresponding compound wherein R 1 2 is CR 3 (0C 1 -3alkyl)C O 2 R 9 ii) AO is CO, reacting in the presence of a strong base a compound of the formula as hereinbefore defined with a compound of the formula WO 93/07137 PCT/GB92/01847 63- R 9 0 2 CC0 2 R 9 wherein R 9 is as hereinbefore defined to form a compound of the formula wherein R 12 is COCO 2 R 9 and R, R 9 R 11 and Ra are as hereinbefore defined, iii) AO is CH(OH), reacting a compound of the formula wherein R 12 is COC02R 9 and R, R 9 R 11 and Ra are as hereinbefore defined with a reducing agent to form the corresponding compound wherein R 12 is CH(OH)C0 2 R 9 iv) AO is CH 2 reacting a compound of the formula wherein R 12 is COCO 2 H or COC02R 9 and R, R 9 R 1 1 and Ra are as hereinbefore defined with a suitable reducing agent to form the corresponding compound wherein R 12 is CH 2 CO 2 H, v) AO is C(OR 5 )(OR 6 reacting a compound of the formula wherein R 12 is COC02R 9 and R, R 9 R 1 1 and Ra are as hereinbefore defined with a C 1 3 alcohol, 1,2-ethanediol or 1,3-propanediol to form the corresponding compound wherein R 1 2 is C(OR 5 )(OR 6 )C0 2 R 9 vi) AO is CF 2 reacting a compound of the formula wherein R 12 is COC02R 9 and R, R 9 R 1 1 and Ra are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R 1 1 is CF 2 CO 2 R 9 or vii) AO is CHF, reacting a compound of the formula wherein R 12 is CH(OH)C0 2 R 9 and R, R 9 R 1 1 and Ra are as hereinbefore defined with a fluorinating agent to form the corresponding compound wherein R 12 is CHFCO 2 R 9 WO 93/07137 PCT/GB92/01847 64 and thereafter optionally o converting the group OR 11 into OH o converting the group AOC0 2 R 9 into ACOC 2 H; or b) for compounds wherein R 1 is CH 2 CO 2 H, converting a compound of the formula (6) a R R 13 O R1 OH Formula (6) wherein R 13 is acetyl and R, and Ra are as hereinbefore defined into the corresponding compound wherein R 13 is CH 2 CO 2 H; or c) for compounds wherein R 1 is CH 2 CH 2 CO 2 H or CH 2 CH 2 CO 2 R 9 hydrogenating a compound of the formula wherein R 13 is CH=CHCO 2 H or CH=CHCO 2 R 9 and thereafter optionally converting the group CH 2 CH 2 CO 2 R 9 into CH 2 CH 2 d0 2 H; or d) for compounds wherein R 1 is PO) (OH)(OR 2 hydrolysing a compound of the formula wherein R 13 is P(O) (OR 2 2 R 2 is as defined in claim 1 and R, and Ra are as hereinbefore defined; or e) for compounds wherein R 1 is P(S)(OH)(OR 2 converting a compound of the formula wherein R 1 3 is P(O) (NHR 1 4 (OR 2 and R 1 4 is phenyl or C 2 6 1 -4alkyl and R, and Ra are as WO 93/07137 PCT/GB92/01847 65 hereinbefore defined into the corresponding compound wherein R 13 is P(S)(OH)(OR 2 or f) for compounds where R 1 is S03H, reacting in the presence of a strong base a compound of the formula as hereinbefore defined with sulphuryl chloride or a chemical equivalent thereof and optionally converting the group OR 11 into OH; or g) for compounds wherein R 1 is SO 2 H, reacting in the presence of a strong base a compound of the formula as hereinbefore defined with sulphur dioxide and optionally converting the group OR 11 into OH; or h) for compounds wherein R 1 is reacting a compound of the formula wherein R 12 is cyano or a compound of the formula wherein R 13 is cyano with an azide salt; or i) for compounds wherein R 1 is 1-(HO 2 CCH 2 )-5-tetrazolyl or 1-(R 9 O 2 CCH 2 )-5-tetrazolyl, reacting a compound of the formula wherein R 13 is 5-tetrazolyl with a compound of the formula (7) LCH 2 CO 2 R 9 (7) wherein L is a leaving group and R 9 is as hereinbefore defined and thereafter optionally converting the group CO 2 R 9 Sto C02H; or j) for compounds wherein R a is halo, reacting a compound of the formula -66- Formula (8) wherein R 15 is a group R 1 as hereinbefore defined or a precursor thereof, and R is as hereinbefore defined, with a suitable halogenating agent, and thereafter if necessary converting a precursor of R 1 to R 1 and optionally thereafter: forming a bioprecursor of RO and/or R 1 forming a pharmaceutically acceptable salt. 2 20 11. Compounds of the formula processes for their preparation or pharmaceutical compositions containing them, substantially as hereinbefore described with reference to the Examples. I i DATED this 22nd day of August, 1994 SmithKline Beecham plc By Its Patent Attorneys DAVIES COLLISON CAVE (14 V 940822,p\oper\dab,26933.spe,66 INTERNATIONAL SEARCH REPORT Interatidonal Applation No PCT/GB 92/0 1847 1. CASSIFICATION OF SU3JECT MATTER (If sevral classification symbos apply, indicate all)6 According to international Patent Classification (IPC) or to both National Classification and [PC Int.Cl. 5 C070401/04; C070213/70; C07F9/58; A61K31/44 //(C07D401/04,257:00, 213:00) U. FIELDS SEARCHED Minimum Documentation Searched 1 Clasificatlon System Classfficatbon Symubols Int.Cl. 5 C07D A61K Documentation Searched other than Minimum Documentation to the Fixtent that such Documents are Included In the Fields Sarchedl X EP,A,O 428 268 (SMITH KLINE FRENCH 1361 LABORATORIES LIMITED) 22 May 1991 see claims 1-5,8,10,12,15-17,20 A see examples 1-10 X EP,A,0 347 027 (SMITH KLINE FRENCH 1-3,6-10 LABORATORIES LIMITED) December 1989 see claims 1-5,8,11-13,16 A see example 5 1-10 ~Special categories of cited documnt :1 toT' later document published after the International filing date or priority date and not in conflict with the aplcation but document defining the pneral state of t an whic isa cited to usderstand the principle or theory underlying the considered to be of particulr revance Ivsil arlier document but published on or after the international IV document of patclrrelevance; the claimed Invention filing date caaot be cniderd oval or cannot be considered to 'V document which may throw doubts on priority claims) or Involv an inventive soep which is cited to esablish the publication date of anothe "P document of particular releunc the claimed invention citation or other special rumso (as speciied) cannot be conidered to inmvov an inventive step when the document referring to an oral disclosure, .me, exchibition or document Is combined with one or mor, other such doer,- other mean tmnu, such combination Idlag obvious to a perim skille '1P document published prior to the International filing date but In the Ut later than the priority date claimed W docomnt member of the sam patent: family IV. CERTIFICATION Date of the Actual Compltion of the International Search Date of Mailing of this International Searc Report 21 DECEMBER 1992 15,D. 93 Internationa searching 4Audtwoity Signatre of Anthmlzad Officer EUROPEAN PATENT OFFCE P. BOSMA M1CI IUiImon ked) J~w 1J-p ,7 :4 J7 A ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION No. GB SA 9201847 65428 This annex fists the patent family me1ber- rehbing to the patent documents cited in the above-mentioned international serc report. The members awe as contained in the European Patent Office EDP file on The European Patent Office is in no way liable for these particulars which are amry given for the purpose of information. 2 1/12/92 0 6' For morm dd-k about thin own: on Offiia Journal of dw Earopema Patent Office, No. 12/32
AU26933/92A 1991-10-11 1992-10-09 Pyridinol derivatives as medicaments Ceased AU654051B2 (en)

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PCT/GB1992/001847 WO1993007137A1 (en) 1991-10-11 1992-10-09 Pyridinol derivatives as medicaments

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DE4323916A1 (en) * 1993-07-16 1995-01-19 Basf Ag Substituted 2-phenylpyridines
DE102004050196A1 (en) 2004-10-15 2006-04-20 Sanofi-Aventis Deutschland Gmbh Substituted 2-pyridone derivatives, process for their preparation and their use as medicaments
CN101602687A (en) * 2008-06-13 2009-12-16 上海特化医药科技有限公司 6-nitro-acetophenone compounds, Preparation Method And The Use

Citations (3)

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Publication number Priority date Publication date Assignee Title
AU616001B2 (en) * 1988-04-21 1991-10-17 Smith Kline & French Laboratories Limited 6-(2-substituted alkyloxy phenyl)-substituted 2-pyridinone derivatives
AU624536B2 (en) * 1989-10-13 1992-06-11 Smith Kline & French Laboratories Limited Substituted(2-alkoxy-phenyl)-2(1H)-pyridinones
AU642743B2 (en) * 1990-05-21 1993-10-28 Smith Kline & French Laboratories Limited Phenol and pyridinol derivatives as pharmaceuticals

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU616001B2 (en) * 1988-04-21 1991-10-17 Smith Kline & French Laboratories Limited 6-(2-substituted alkyloxy phenyl)-substituted 2-pyridinone derivatives
AU624536B2 (en) * 1989-10-13 1992-06-11 Smith Kline & French Laboratories Limited Substituted(2-alkoxy-phenyl)-2(1H)-pyridinones
AU642743B2 (en) * 1990-05-21 1993-10-28 Smith Kline & French Laboratories Limited Phenol and pyridinol derivatives as pharmaceuticals

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PT100949A (en) 1994-06-30
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