Roussel Uclaf

Cyclacel Limited

Other

Robert Westwood

Peter D Kennewell

Stephen Clements-Jewery

Elizabeth A Kuo

Wilfred R Tully

David A Rowlands

Robert K Smalley

Abdul B Luheshi

Robert R Bartlett

Julian Scott Northen

Rudolf Schleyerbach

Derek John Londesbrough

David P Kay

John Bodenham Taylor

Saroop Singh Matharu

Robert Murdoch

Gavin Wood

Benjamin Mark Skead

Takashi Takita

Daniella I Zheleva

Stuart Donald Jones

Peter Wilfred Hairsine

Jonathan Charles Christian Atherton

Ian R Ager

Eiji Numagami

Mark Thomas

Janice McLachlan

Kenneth Duncan

Peter Miller

Alistair Selkirk

Fred Scaerou

Matharu S Singh

Tsuyoshi Murofushi

Chris Atherton

Gavin Jeffrey Wood

Ben Skead

The present invention relates to a process for preparing a compound of formula [I], said process comprising the steps of: formula [II]+formula [III]&#x2192;formula [I] (i) forming a reaction mixture comprising (a) a compound of formula [II], (b) a compound of formula [III] and (c) 1,2-propanediol or polyethylene glycol, or a mixture thereof, and optionally (d) a base; (ii) heating said reaction mixture to a temperature of at least about 150&#xb0; C. to form a compound of formula [I]; (iii) isolating said compound of formula [I]; and (iv) optionally converting said compound of formula [I] into salt form; wherein: Rand Rare each independently H, alkyl or haloalkyl; Rand Rare each independently H, alkyl, haloalkyl or aryl; Ris alkyl, alkenyl, cycloalkyl or cycloalkyl-alkyl, each of which may be optionally substituted with one or more OH groups; Ris selected from cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclobutylmethylamino and formula (A) where one of X, Y and Z is N and the remainder are CR; R, Rand each Rare independently H, alkyl or haloalkyl, wherein at least one of R, Rand Ris other than H. Further aspects of the invention relate to a highly diastereoselective process for the preparation of compounds of formula [III], a process for preparing intermediates of formula [II], and other intermediates useful in the synthesis of compounds of formula [I], and to a process for preparing the crystalline tartrate salt and free base of compounds of formula [I]. 

Process for preparing purine derivatives

The present invention relates to a process for preparing a compound of formula 682-4, said process comprising the steps of: (i) converting a compound of formula 682-1 into a compound of formula 682-2; (ii) converting said compound of formula 682-2' into a compound of formula 682-3; and (iii) converting said compound of formula 682-3 into a compound of formula 682-4. Further aspects of the invention relate to the use of the above process in the preparation of 2&#x2032;-cyano-2&#x2032;-deoxy-N-palmitoyl-1-&#x3b2;-D-arabmofuranosylcytosine, a pyrimidine nucleoside which is therapeutically useful in the treatment and/or prevention of cancer. 

Preparation of intermediates useful in the synthesis of 2'-cyano-2&#x2032;-deoxy-N4-palmi-toyl-1-&#x3b2;-D-arabinofuranosylcytosine

The present invention relates to a pharmaceutical formulation which comprises (i) a capsule, and (ii) a core comprising crystalline 2'-cyano-2&#x2032;-deoxy-N-palmitoyl-1-&#x3b2;-D-arabinofuranosylcytosine and a liquid carrier.

Crystalline pyrimidine nucleoside derivative suspensions in capsules

The present invention relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein Z is NR, NHCO, NHSO, NHCH, CH, CHCH, or CH&#x2550;CH; X is a hydrocarbyl group optionally substituted by one or more Rgroups; Rand Rare each independently II or alkyl; R-Rare each independently II or (CII)R, where m is O, 1, 2, or 3; each Ris independently (CH)R, where each Ris independently selected from O(CH)R, R, COR, COOR, CN, CONRR, NRR, NRCOR, SR, SOR, SOR, NRSOR, SOOR, SONRR, halogen, CF, and NO, and wherein each a is 0, 1, 2, or 3 and b is 0, 1, 2, or 3; Rand Rare each independently H or (CH)R, where n is 0, 1, 2, or 3; and each Ris independently selected from alkyl, cycloalkyl, heteroaryl, aralkyl, aryl and heterocycloalkyl, each of which may be optionally substituted by one or more substituents selected from halogen, OH, CN, COO-alkyl, aralkyl, SO-alkyl, SO-aryl, COOH, CO-alkyl, CO-aryl, NH, NH-alkyl, N(alkyl), CF, alkyl and alkoxy, wherein said alkyl and alkoxy groups may be further substituted by one or more OH groups. Further aspects of the invention relate to pharmaceutical compositions comprising compounds of formula I, and the use of compounds of formula (I) in the preparation of a medicament for treating a variety of disorders, including proliferative disorders, viral disorders, stroke, etc. 

Pyrimidin-4-yl-3, 4-dihydro-2H-pyrrolo [1,2A] pyrazin-1-one compounds

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R.sub.1 is hydrogen or alkyl of 1 to 3 carbon atoms; R.sub.2 is cycloalkyl of 3 to 6 carbon atoms; R.sub.4 is selected from the group consisting of halogen, nitrile, nitro, --SCH.sub.3, -alkylcarbonyl of 1 to 6 carbon atoms, cycloalkylcarbonyl of 3 to 6 carbon atoms, --CX.sub.3, 'WCX.sub.3, --(CH.sub.2).sub.n CX.sub.3, --(CX.sub.2).sub.n CX.sub.3, --W(CX.sub.2).sub.n CX.sub.3 and a --W(CH.sub.2).sub.n CX.sub.3, in which X is halogen, W is oxygen or sulfur, and n is 1, 2 or 3; and R.sub.5 is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms and cycloalkyl of 3 to 6 carbon atoms; with the proviso that if R.sub.5 is hydrogen, R.sub.4 is not --SCH.sub.3 or --CF.sub.3 and their non-toxic pharmaceutically acceptable salts having anti-prolifera-tive, anti-inflammatory and anti-tumor activity.

Isoxazoles

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R.sub.1 is hydrogen or alkyl of 1 to 3 carbon atoms; R.sub.2 is cycloalkyl of 3 to 6 carbon atoms; R.sub.4 is selected from the group consisting of halogen, nitrile, nitro, --SCH.sub.3, -alkylcarbonyl of 1 to 6 carbon atoms, cycloalkylcarbonyl of 3 to 6 carbon atoms, --CX.sub.3, --WCX.sub.3, --(CH.sub.2).sub.n CX.sub.3, --(CX.sub.2).sub.n CX.sub.3, --W(CX.sub.2).sub.n CX.sub.3 and a --W(CH.sub.2).sub.n CX.sub.3, in which X is halogen, W is oxygen or sulfur, and n is 1, 2 or 3; and R.sub.5 is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms and cycloalkyl of 3 to 6 carbon atoms; with the proviso that if R.sub.5 is hydrogen, R.sub.4 is not --SCH.sub.3 or --CF.sub.3 and their non-toxic pharmaceutically acceptable salts having anti-prolifera-tive, anti-inflammatory and anti-tumor activity.

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R.sub.1 is hydrogen or alkyl of 1 to 3 carbon atoms, R.sub.2 is alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, R.sub.3 is --COOR.sub.6, R.sub.6 is hydrogen or alkyl of 1 to 3 carbon atoms, R.sub.4 is selected from the group consisting of halogen, --CN, --NO.sub.2, --SCH.sub.3, alkylcarbonyl of 1 to 6 alkyl carbon atoms, --CX.sub.3, --WCX.sub.3, --(CH.sub.2).sub.n --CX.sub.3, --(CX.sub.2).sub.n --CX.sub.3, --W--(CX.sub.2).sub.n --CX.sub.3, and --W--(CH.sub.2).sub.n --CX.sub.3, X is halogen, W is --O-- or --S--, n is 1, 2 or 3, R.sub.5 is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms and cycloalkyl of 3 to 6 carbon atoms and their salts with non-toxic pharmaceutically acceptable bases with the proviso that if R.sub.2 is alkyl of 1 to 3 carbon atoms, R.sub.1 is hydrogen and R.sub.4 is selected from the group consisting of halogen, --CX.sub.3, --(CH.sub.2).sub.n --CX.sub.3, --(CX.sub.2).sub.n --CX.sub.3, --OCX.sub.3, --O--(CX.sub.2).sub.n --CX.sub.3, and --O--(CH.sub.2).sub.n --CX.sub.3, X is halogen and n is 1, 2 or 3, R.sub.5 cannot be hydrogen having anti-inflammatory activity and their preparation and intermediates.

Phenyl carboxamide isoxazoles

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R.sub.1 and R.sub.2 are individually selected from the group consisting of hydrogen, alkyl and hydroxyalkyl of 1 to 5 carbon atoms and amino, n is an integer from 1 to 3, X and X.sub.1 are individually selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms or taken together with the carbon atom to which they are attached are ##STR2## Y is --O-- or --S--, R.sub.3 is alkyl of 1 to 3 carbon atoms or aryl of 6 to 8 carbon atoms, ##STR3## is selected from the group consisting of ##STR4## R.sub.4 and R.sub.5 are individually aryl unsubstituted or substituted with at least one member of the group consisting of halogen, --NO.sub.2 and alkyl and alkoxy of 1 to 3 carbon atoms and non-toxic, pharmaceutically acceptable salts thereof with acids and bases having cyclooxygenase inhibiting and antibiotic acitvity.

Process for the preparation of azabicyclo compounds

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R.sub.1 and R.sub.2 are individually selected from the group consisting of hydrogen, alkyl and hydroxyalkyl of 1 to 5 carbon atoms and amino, n is an integer from 1 to 3, X and X.sub.1 are individually selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms or taken together with the carbon atom to which they are attached are &gt;C.dbd.O Y is --O-- or --S--, R.sub.3 is alkyl of 1 to 3 carbon atoms or aryl of 6 to 8 carbon atoms, ##STR2## is selected from the group consisting of ##STR3## R.sub.4 and R.sub.5 are individually aryl unsubstituted or substituted with at least one member of the group consisting of halogen, --NO.sub.2 and alkyl and alkoxy of 1 to 3 carbon atoms and non-toxic, pharmaceutically acceptable salts thereof with acids and bases having cyclooxygenase inhibiting and antibiotic activity.

Azabicyclo compounds

A compound selected from the group consisting of 8-phenylthio-tetrahydroquinolines of the formula ##STR1## wherein R.sub.1 and R.sub.2 are individually selected from the group consisting of hydrogen, halogen, alkyl of 1 to 6 carbon atoms optionally substituted with hydroxy, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms, --OH, --NO.sub.2, --NH.sub.2, --COOH, --CN and aminosulfonyl or when R.sub.1 and R.sub.2 are on adjacent carbon atoms form with the said carbon atoms phenyl and their non-toxic, pharmaceutically acceptable acid addition salts having anti-allergic activity.

8-phenylthio-tetrahydroquinolines and anti-allergic use thereof

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R.sub.1, R.sub.2 and R.sub.3 are individually selected from the group consisting of hydrogen, halogen and alkyl and alkoxy of 1 to 6 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts having anti-allergic and anti-inflammatory properties.

Novel benzimidazolyl-thiomethyl-benzothiazoles

Novel 8-thiotetrahydroquinolines of the formula ##STR1## wherein X is selected from the group consisting of ##STR2## Alk is alkyl of 1 to 6 carbon atoms, R.sub.1 and R.sub.2 are Alk individually selected from the group consisting of hydrogen and aryl or taken together with the carbon atoms to which they are attached form a phenyl optionally substituted with at least one member of the group consisting of alkyl, alkoxy and alkylthio of 1 to 6 carbon atoms, halogen, ##STR3## and Alk' is alkyl of 1 to 6 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts having antiallergic activity and their preparation.

8[2-(imidazolyl)thio] and

Novel pyrimidines of the formula ##STR1## wherein R.sub.1 is selected from the group consisting of --OH, cation of metals and organic bases, alkoxy of 1 to 5 carbon atoms, hydrazino and 1H-tetrazol-5-yl-amino, A is selected from the group consisting of ##STR2## R.sub.2 is selected from the group consisting of hydrogen and alkyl of 1 to 5 carbon atoms and R.sub.3 and R.sub.4 are individually selected from the group consisting of hydrogen, halogen and alkyl and alkoxy of 1 to 5 carbon atoms with the proviso that when R.sub.1 is alkoxy of 1 to 5 carbon atoms, R.sub.2 is not hydrogen and their non-toxic, pharmaceutically acceptable acid addition salts having anti-allergic properties.

Antiallergic pyrimido[1,2-a]quinoxalin-2-carboxylic acid derivatives

Novel triazoloquinazolones of the formula ##STR1## wherein R and R' are individually selected from the group consisting of hydrogen, halogen, nitro and alkyl and alkoxy of 1 to 3 carbon atoms, Y is selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 8 carbon atoms and aralkyl of 7 to 8 carbon atoms, B is an alkylene of 1 to 3 carbon atoms, X is selected from the group consisting of ##STR2## R.sub.1 and R.sub.2 are individually selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, aryl of 6 to 8 carbon atoms, aralkyl of 7 to 8 carbon atoms, aminoalkyl of 2 to 4 carbon atoms, mono- and dialkylaminoalkyl with each alkyl having 2 to 4 carbon atoms, piperidinoalkyl of 1 to 4 alkyl carbon atoms, morpholinoalkyl of 1 to 4 alkyl carbon atoms and piperazinylalkyl of 1 to 4 alkyl carbon atoms or R.sub.1 and R.sub.2 taken together with the nitrogen to which they are attached form a saturated mono- or bicyclic heterocyclic ring with 4 to 8 carbon atoms optionally substituted with 1 to 2 methyls and optionally containing in the ring a heteroatom selected from --O--, --S-- and ##STR3## and R.sub.3 is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, hydroxyalkyl of 1 to 3 carbon atoms, alkoxycarbonyl of 2 to 5 carbon atoms, aryl of 6 to 8 carbon atoms and aralkyl of 7 to 8 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts having antihistaminic and bronchospasmolytic activity and their preparation and intermediates.

Triazoloquinazolones having antihistaminic and bronchospasmolytic

Novel compounds selected from the group consisting of compounds of the formula ##STR1## wherein R.sub.1 is selected from the group consisting of hydrogen and alkyl of 1 or 5 carbon atoms, R.sub.2 is selected from the group consisting of hydrogen, halogen and methyl, R.sub.3, R.sub.4 and R.sub.5 are individually selected from the group consisting of hydrogen, halogen, alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 3 carbon atoms, --NH.sub.2 and mono- and dialkylamino of 1 to 3 alkyl carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts having antidepressant and neuroleptic activity and their preparation.

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Oxon, United Kingdom

Robert Westwood