Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
  • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D497/04—Ortho-condensed systems
• • 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
  • A61P17/06—Antipsoriatics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• the present invention relates to methods for preparing ttaazolopyrimidine compounds, intermediate compounds used in such methods, t azolopyrrmidine compounds so prepared and their use in therapy.
• O-01/25242 we describe pharmaceutically active compounds of the general formula I
• Such methods include treatment of a compound of formula
• R 1 represents a C 3 -C carbocyclic, -C 8 alkyl, C 2 -C 6 alkenyl or C 2 -C6 alkynyl group, each of the groups being optionally substituted by one or more substituent groups independently selected from halogen atoms, -OR 4 , -NR 5 R 6 , -CONR 5 R 6 , -COOR 7 , -NR 8 COR 9 , -SR 10 , -SO 2 R 10 , -SO 2 NR 5 R 6 , -NR 8 SO 2 R 9 or an aryl or heteroaryl group, both of which may be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, -OR 4 , -NR 5 R 6 , -CONR 5 R 6 , -COOR 7 , -NR 8 COR 9 , -SR 10 , -SO 2 R 10 , -SO 2 NR 5 R 6 , each
• R 4 represents hydrogen, C ⁇ -C 6 alkyl or a phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, -OR 11 and -NR 12 R 13 .
• R 5 and R 6 independently represent a hydrogen atom or a C ⁇ -C 6 alkyl or phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, -OR 14 and -NR 15 R 16 , -CONR 15 R 16 , -NR 15 COR 16 , -SONR 15 R 16 , NR 15 SO 2 R 16 or
• R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to
• 7-membered saturated heterocyclic ring system optionally contaming a further heteroatom selected from oxygen and nitrogen atoms, which ring system may be optionally substituted by one or more substituent groups independently selected from phenyl, -OR 14 , -COOR 14 , -
• NR 15 R 16 -CONR 15 R 16 , -NR 15 COR 16 , -SONR 15 R 16 , NR 15 SO 2 R 16 or Ci-C ⁇ alkyl, itself optionally substituted by one or more substituents independently selected from halogen atoms and -NR 15 R 16 and -OR 17 groups;
• R 10 represents a hydrogen atom or a Ci-C ⁇ -alkyl or a phenyl group, the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, -OR 17 and -NR 15 R 16 ; and each of R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 R 15 , R 16 , R 17 independently represents a hydrogen atom or a C ⁇ -C 6 alkyl, or a phenyl group; which method comprises contacting
• L is a leaving group with a thiazole nitrogen protecting group reagent under appropriate reaction conditions to form a compound of the formula
• Example 3(d) where a particular diol is introduced and protected via the compound (2,2,5-trimethyl- 1 ,3-dioxan-5-yl)amine.
• Convenient protecting groups will be apparent to the chemist of ordinary skill. It will be appreciated that the more stable the resulting product upon protection the likelihood of increased difficulty in removing the protecting group afterwards. Additionally, some resulting products upon protection may not be sufficiently stable to isolation by standard laboratory methods. The protection and deprotection of functional groups is fully described in 'Protective Groups in Organic Synthesis', 2nd edition, T. W. Greene & P. G. M. Wuts, Wiley-Interscience (1991).
• suitable protecting groups for the given transformations, to provide compounds of formula I, involving removal under appropriate hydrolytic conditions are [with suitable protecting group agents indicated in square brackets] methoxymethyl [chloromethyl methyl ether], and particularly etl oxymethyl [chloromethyl ethyl ether or diethoxymethane], benzyloxymethyl [benzyl chloromethyl ether], pivaloyloxymethyl [chloromethyl pivalate], 2-(trimethylsilyl)ethoxymethyl [2-(trimethylsilyl)ethoxymethyl chloride], l-(ethoxy)ethyl [ethyl vinyl ether] and 2-tetrahydropyranyl [3,4-dihydro-(2H)-pyran].
• Each individual protecting group listed above and its use represents a particular independent aspect of the invention.
• Base-assisted removal of the 2-(phenylsulfonyl)ethyl [phenyl vinyl sulfone] protecting group under non-aqueous conditions is a suitable method for achieving these transformations.
• the approach is also suited to catalytic reduction methods for removal of appropriate protecting groups.
• Such protecting groups include benzyl, diphenylmethyl, triphenylmethyl and benzyloxymethyl. Allyl as a protecting group can be removed under metal-assisted conditions and 4-methoxybenzyl, 2,4-dimethoxybenzyl and di(4-methoxyphenyl)methyl can be removed under oxidative conditions.
• Acyl, benzoyl, pyrrohdinym ethyl and urea-type protecting groups are other examples that can be removed under appropriate hydrolytic conditions.
• Representative chloroformate reagents do not yield a carbamate protecting group, for example a benzylchloroformate reagent is found to yield a benzyl protecting group.
• an alkyl or alkenyl group or an alkyl or alkenyl moiety in a substituent group may be linear or branched.
• Aryl groups include phenyl and naphthyl.
• Heteroaryl groups include 5- or 6-membered aromatic rings containing one or more heteroatoms selected from N, S, and O.
• R 1 represents benzyl or benzyl substituted by one or more Ci-C ⁇ alkyl, C ⁇ -C 6 alkoxy or halogen atoms.
• R 2 and R 3 represent a group substituted by one or more 3-8 membered rings optionally containing one or more atoms selected from O, S or NR 8 , examples of such groups include piperidine, pyrrolidine, piperazine and morpholine.
• one of R 2 or R 3 is hydrogen and the other is C ⁇ -C 8 alkyl substituted by hydroxy and one or more methyl or ethyl groups.
• R 2 or R 3 is hydrogen and the other is CH(CH 3 )CH 2 OH, CH(Et)CH 2 OH, C(CH 3 ) 2 CH 2 OH or CH(CH 2 OH) 2 .
• R 2 or R 3 is hydrogen and the other is CH(CH 3 )CH 2 OH or CH(Et)CH 2 OH the resulting compounds of formula (I) are particularly in the form of the (R) isomer.
• Particular compounds of the formula I for use in the method of the invention include those wherein R 1 represents a (2,3-difluorophenyl)methyl group and R 2 and R 3 together represent a C ⁇ -8 alkyl group optionally substituted by one or more substituent groups independently selected from -OR 4 wherein R 4 represents hydrogen or a C ⁇ -6 alkyl group.
• Further particular compounds of the formula I include compounds of the formula la
• each R x is independently selected from hydrogen, a alkyl group optionally substituted by hydroxy, arnino, -O-C M alkyl, -S-Cw alkyl, alkyl, -NHSO 2 R, or - CONR 2 and provided that bo th R x are not hydro gen or amino. More particular compounds of the invention are wherein each R is independently selected from hydrogen and hydroxymethyl, provided that both R x are not hydrogen.
• the invention also provides novel salts of the above compounds namely the potassium salt of the compound wherein one R x is hydrogen and the other is hydroxymethyl (cf. Example 2) and both the sodium and potassium salts of the compound wherein both R are hydroxymethyl (Examples 3 and 4).
• Compounds of the formula II are novel and represent a further aspect of the invention.
• Preparation of a compound of the formula I via deprotection of a compound of the formula II is novel and represents a further aspect of the invention.
• Compounds of the formula III are novel and represent a further aspect of the invention.
• Preparation of a compound of the formula II via reaction of a compound of the formula III with an amine of formula HNR 2 R 3 is novel and represents a further aspect of the invention.
• Compounds of the formula IN are novel (except for 7-chloro-5-[[(2,3- difluorophenyl)methyl]tl ⁇ o]tMazolo[4,5-d]pyrinddm-2-(3H)-one) and represent a further aspect of the invention. They are conveniently prepared by reaction of a compound of formula
• halocarbonylsulfenylhalide a halocarbonylsulfenylhalide.
• Convenient halogen atoms are independently selected from chlorine and bromine, chlorine is a preferred halogen atom and chlorocarbonylsulfenylchloride is a preferred reagent.
• Such reaction represents a further independent aspect of this invention.
• Compounds of formula VI are novel and represent a further, independent aspect of the invention, they are conveniently prepared by reaction of a compound of formula
• the reaction mixture was heated to reflux and maintained at this temperature for 36 hours, before cooling to ambient temperature and adding to water (25ml) at 50 °C with stirring over 30 minutes.
• An additional acetonitrile (5ml) rinse of the reaction vessel was added to the drown-out mixture, before heating to 75 °C. and slowly cooling to 25 °C at ⁇ 0.5 °C/min.
• the resulting mixture was held at 25 °C for 30 minutes and then collected by filtration, washing four times with water (25ml), to afford the title compound as an off-white solid (3.5g).
• Phenylvinylsulfone (20g, 1.3eq) was dissolved in butyronitrile (80ml) in a separate flask and this solution was added to the vessel, followed by a line wash with butyronitrile (70ml). The orange solution was heated to an internal temperature of 100°C. After 18 hours HPLC showed almost complete consumption of the starting material (3.36% 7-c oro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5- d]pyrimidin-2-(3H)-one remained)*.
• the reaction was allowed to cool from 100 to 50°C over 6.5hrs and held at 50°C under nitrogen for 64 hrs. In order to get a homogeneous sample the reaction was re-heated to 100°C (1.19% 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]-3-[2- (phenylsulfonyl)ethyl]tMazolo[4,5--i] ⁇ yrimidin-2-(3H)-one present by HPLC). The reaction was cooled from 100 to 50°C over 1 hr and water (200mLs) was added. A precipitate was observed. The mixture was cooled from 50°C to 20°C over 2 hrs.
• the precipitate was 'aged' at 20°C for 1 hr and collected by filtration.
• the 'cake' was washed with 1:1 water/butyronitrile (70ml) twice, then with butyronitrile (35ml).
• the solid was then dried on the filter for 30mins, collected and dried in a vacuum oven overnight at 50°C.
• the sample showed almost complete consumption of the starting material (0.36% 5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(lR)-2- hydroxy-l-methylethyl]amino]-3-[2-(phenylsulfonyl)ethyl]tMazolo[4,5--i]pyrimidm-2-(3H)- one remained).
• Example 3 1H NMR: ⁇ (DMSO-d6) 1.06 (d, 3H), 3.26-3.43 (m, 2H), 4.09 (quin, IH), 4.34 (m, 2H), 4.65 (bs, IH), 5.59 (d, IH), 7.12 (q, IH), 7.28 (q, 1H), 7.37 (t, IH).
• the compound of Example 1(e) may be reacted with potassium hydroxide to give the title compound.
• Example 3 1H NMR: ⁇ (DMSO-d6) 1.06 (d, 3H), 3.26-3.43 (m, 2H), 4.09 (quin, IH), 4.34 (m, 2H), 4.65 (bs, IH), 5.59 (d, IH), 7.12 (q, IH), 7.28 (q, 1H), 7.37 (t, IH).
• the compound of Example 1(e) may be reacted with potassium hydroxide to give the title compound.

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