NZ211104A

NZ211104A - Pybenzothiazoles and pharmaceutical compositions

Info

Publication number: NZ211104A
Application number: NZ211104A
Authority: NZ
Inventors: D A Rowlands; J M C Golec
Original assignee: Roussel Uclaf
Priority date: 1984-02-13
Filing date: 1985-02-12
Publication date: 1987-08-31
Also published as: HUT38649A; GB2154583B; EP0153230B1; PT79955A; GR850369B; ES8800243A1; FI850582L; GB8403739D0; PT79955B; CA1257259A; DE3571621D1; ZA85696B; ES553574A0; FI79323C; ATE44745T1; EP0153230A3; GB8503541D0; ES540332A0; AU3867285A; FI850582A0

Abstract

Compounds of formula I <IMAGE> [wherein R and R3,which may be the same or different, each represents a hydrogen atom or a straight or branched C1-6 alkyl group or together with the intervening carbon atom represent a C3-6 cycloalkyl group; R1 represents a hydroxy group, a straight or branched C1-6 alkoxy group or a group of formula <IMAGE> (wherein R5 and R6, which may be the same or different, each represents a hydrogen atom or a C1-6 alkyl group or together with the intervening nitrogen atom represent a piperidino or morpholino group); and R2 represents a hydrogen atom, a straight or branched C1-16 alkyl group, a C2-7 alkoxycarbonyl group, a C3-6 cycloalkyl group, an aralkyl group, an aryl group (unsubstituted or substituted by one or more halogen atoms or C1-6 alkyl, C1-6 alkoxy or nitro groups), or a heteroaryl group] and salts thereof are antiallergic agents.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £11104 f 211104 t—' d J J Priori^ Date's;: . C: \lrlrS5 C!;,,CO?P^5iCMJQ:. p.ei^MvQS.. p. p1 3 1 AUG 1987 |2^C) PATENTS FORM NO. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "CHEMICAL COMPOUNDS" If WE ROUSSEL-UCLAF a French Body Corporate of 35 Boulevard des Invalides, 75007 Paris, France hereby declare the invention, for which f/we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by I I the following statement:- j i -1- (followtd by psgt I A.) I f I c t - lUr- * % f- ' Chemical Compounds The present invention relates to novel pyrimido [2,1-b]benzothiazoles and salts thereof, processes 5 for their preparation, and their application as drugs. We have found certain novel pyrimido [2,1-b]benzoth iazoles to possess interesting pharmacological properties, in particular antiallergic activities. 10 Accordingly, in one aspect the invention provides novel pyrimido {2,1-b]benzothiazoles of formula I R- (I) [wherein R and R^, which may be the same or different, 15 each represents a hydrogen atom or a straight or branched alkyl group or together with the intervening carbon atom represent a cycloalkyl group; R^ represents a hydroxy group, a straight or branched C^_g alkoxy group or a group of formula 20 ^R5 (A) ^R6 (wherein R^ and Rg, which may be the same or different, each represents a hydrogen atom or a alkyl 25 group or together with the intervening nitrogen atom represent a piperidino or morpholino group); and represents a hydrogen atom, a straight or branched C^_g alkyl group, a C2_7 alkoxycarbonyl group, a C^_g cycloalkyl group, an aralkyl ^grou^, _ ' } ""y an aryl group (un3ubstituted or subst-ituted" by one or more halogen atoms or C^_g alkyl, C^_g alkoxy 5 or nitro groups), or a heteroaryl group] and salts thereof. In respect of focmula I above, where straight or branched alkyl groups are referred to, these may for example be methyl, ethyl, propyl, 10 isopropyl, butyl, isobutyl, pentyl or hexyl groups. Straight or branched C^_g alkoxy groups may for example be methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy or hexyloxy groups. ^2-6 cy0*-0*!^! groups may for example be cyclohexyl groups. Aralkyl 15 groups may for example be benzyl groups. Aryl groups may for example be Cg_j^ groups such as phenyl or naphthyl groups. C2-7 alk°*ycacbony*■ groups may for example be methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl groups. Where halogen atoms 20 are referred to, these may for example be chlorine, fluorine or bromine atoms. Heteroaryl groups may contain one or more hetero, e.g. sulphur, atoms in the aryl ring and may be for example 2-thienyl groups. 25 The compounds of formula I wherein R^ represents a hydroxy group are acidic in character and can form salts with metals or nitrogen bases. Salts with metals may for example be salts with alkali metals, for example sodium, potassium and lithium, 30 with alkaline earth metals, for example calcium or salts with metals such as aluminium and magnesium. Salts with nitrogen bases include, for example, ammonium salts and salts with amines, e.g. tromethamine and triethanol-amine, and with lysine and arginine. The compounds of formula I in which represents an alkoxy group or a group of formula (A) are basic in character and may form acid addition salts. The acid addition salts may be formed with inorganic or organic acids ; they may, for example, be salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic and aspartic * ^ r, A y :j i ' i) acids, alkane-sulphonic acids (eg methanesulphonic acid) and arylsulphonic acids (eg benzenesulphonic acid). Such salts may however be susceptible to hydrolysis to form the free base in water. As examples of the preferred compounds of the invention, particular reference may be made 5 to those compounds of formula I and salts thereof in which one or both of R and R^ represent hydrogen atoms or methyl or ethyl groups. Also as examples of preferred compounds of the invention mention may be made of those compounds 10 of formula I and salts thereof wherein one or both of R and R^ represent hydrogen atoms or methyl or ethyl groups and R2 represents a hydrogen atom, a straight-chain or branched C^_g alkyl group, a methoxycarbonyl group or a phenyl group optionally 15 substituted by one or more halogen atoms or methyl, methoxy or nitro groups. Especially preferred compounds of the invention are for example: ethyl 2-oxo-4-phenyl-2H-pyr imidoI2,1-b]benzo-20 thiazole-8-acetate; ethyl 2-oxo-4-(p-methoxyphenyl)-2H-pyrimido[2,l-b]-ben2oth iazole-8-acetate; ethyl 2-0x0-4-(o-chlorophenyl)-2H-pyrimido[2,1-b]-benzothiazole-8-acetate; 25 ethyl a-methyl-2-oxo-4-phenyl-2H-pyrimido(2,1-b] benzoth iazole-8-acetate; ethyl a-methyl-2-oxo-4-(p-chlorophenyl)-2H-pyr imido[2,1-b]benzoth iazole-8-ace ta te; ethyl a-ethyl-2-oxo-4-phenyl-2H-pyrimido[2,1-b] 30 benzothiazole-8-acetate; and salts of these compounds. In a further aspect, the invention provides a process for the preparation of novel pyrimido[2,1-b]-benzothiazoles of formula I wherein R^ is a hydroxy 35 or alkoxy group and salts thereof, which process comprises reacting a compound of formula II •J 4 N *IH 2 (ii) R 3 :or1 ' (wherein R and R^ are as hereinbefore defined and Rj^ represents a hydroxy group or a alkoxy 5 group, preferably a C^_g alkoxy group) with a compound of formula III (wherein R2 is as hereinbefore defined and R^ represents an alkyl group, preferably a C1-3 alkyl group) 10 followed if desired by the isolation of, and/or formation of a salt of, the compound of formula I thus obtained. Compounds of formula I in which R^ represents a group of formula (A) may, for example, be prepared 15 by reaction of a compound of formula I in which R^ represents a hydroxy group with a compound of formula R2-CaC-C02R4 (III) 20 (B) (wherein R^ and Rg are as hereinbefore defined) in the presence of 1,1 *-carbonyldiimidazole. Such I * 1 1 f> ,£ - 5 - a process constitutes a further feature of the present invention. Compounds of formula I wherein R^ represents a hydroxy group, whilst being compounds of the 5 invention in their own right/ may also be used as intermediates for the preparation of further compounds of the invention, for example by ester ification by reaction with an alcohol of formula IV HO - R"L (IV) 10 (wherein represents a C^_g alkyl group). Similarly, compounds of formula I wherein R^ represents an alkoxy group may also be used as intermediates in the preparation of further compounds of the invention, for example by the 15 following processes which also constitute further features of the invention: i) transesterifying a compound of formula I wherein represents a C^_g alkoxy group with an alcohol of formula IV 20 HO - R"x (IV) wherein R"^ represents a different alkyl group; and ii) deesterifying a compound of formula I wherein R^ represents a alkoxy group to obtain a compound 25 of formula I wherein R^ represents a hydroxy group. The above processes of the invention are preferably carried out in the following manner: The reaction of the 2-aminobenzothiazole of formula II with the propiolate of formula III <-«w f- may be, and where Rj is hydrogen preferably is, effected under reflux and in the presence of an alcohol such as ethanol and a catalyst such as palladium. However, where in the propiolate of 5 formula III Rj is other than hydrogen, the reaction is preferably effected under heating, e.g to 100-180*C, and in the absence of a solvent. The deesterifi-cation of a compound of formula I wherein represents alkoxy group is suitably effected with the use 10 of a weak base such as potassium carbonate. Salts with metal ions or nitrogen bases of compounds of formula I wherein R^ is a hydroxy group may be prepared by reacting the said compounds of formula I with an appropriate base, such as 15 an alkali metal, alkali earth metal or nitrogen base. Salts with acids of compounds of formula I wherein Rj is an alkoxy group or a group of formula -NR&R6 may be prepared by reacting the said compounds of formula I with an appropriate acid. The compounds of the present invention have interesting pharmacological properties. In particular, compounds which have been tested exhibit remarkable 20 antiallergic properties. These properties are illustrated by experimental test results given hereinafter. It will be appreciated therefore that the compounds of the invention may be useful in medicine. For pharmaceutical use, it will of 25 course be the case that the salts of the compounds of formula I will be physiologically acceptable. Other salts may however find use, for example, in the preparation of compounds of formula I and their physiologically acceptable salts. 30 The invention accordingly further provides compounds of formula I and physiologically acceptable salts thereof for use in the treatment of allergy in the human or animal body. Preferred in this connection are compounds 35 of formula I wherein one or both of R and represent hydrogen atoms or methyl or ethyl groups and pharmacologically acceptable salts of such compounds. Especially preferred are compounds of formula I wherein one or both of R and Rj represent hydrogen atoms or methyl or ethyl groups and R2 represents a hydrogen atom, a alkyl group, a methoxycarbonyl group or a phenyl group optionally substituted by one or more halogen atoms or methyl, nitro or methoxy groups and the physiologically acceptable salts of such compounds. Particularly suitable for use as medicaments are the following compounds: ethyl 2-oxo-4-phenyl-2H-pyrimido(2,1-b]benzoth iazole-8-acetate; ethyl 2-oxo-4-(p-methoxyphenyl)-2H-pyrimido[2,1-b] -benzothiazole-8-acetate; ethyl 2-0x0-4-(o-chloropheny1)-2H-pyrimido[2,1-b]-benzothiazole-8-acetate; ethyl a-methyl-2-oxo-4-phenyl-2H-pyrimido(2,1-bl benzothiazole-8-acetate; ethyl a-methyl-2-oxo-4-(p-?hlorophenyl)-2H- b pyriraidof2,1-b]benzothiazole-8-acevate ; ethyl a-ethyl-2-oxo-4-phenyl-AH-pyr imido-[2,1-b]benzoth iazole-8-acetate; and their physiologically acceptable salts. Such compounds may have utility for example in the treatment of allergic asthma and asthmatiform bronchitis of allergic origin. ^the invention provides the use of compound,s--of__formula I or physiologically acceptable salts thereof fortHe~~1rp«a£itient of allergy in the human or animal body. ~ , In another aspect, the invention provides pharmaceutical compositions containing as active ingredient at least one compound of formula I or a physiologically acceptable salt thereof in admixture with at least one pharmaceutical carrier and/or exc ipient. For pharmaceutical administration, the compounds 26 JUN1987 I - 8 - of formula r and their physiologically acceptable salts may for example be incorporated in compositions for oral, rectal and parenteral (including topical) administration, optionally in administration with 5 other active ingredients. The pharmaceutical compositions may be for example solids or liquids, presented in conventional form for use in human or animal medicine, for example tablets, (including plain or coated tablets), gelatine capsules, granules, 10 suppositories, syrups, aerosols, creams, ointments and injectable preparations, prepared in conventional manner. The active ingredient (s) may be used in conjunction with excipients customarily employed in pharmaceutical 15 compositions for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, animal or vegetable fats, paraffin derivatives, glycols, and various wetting, dispersing or emulsifying agents and/or preservatives. 20 Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply y-'-\ „ ? >. / ^1 ... \ a fixed dose of active ingredient. Suitable dosage/ '-\ / v \ units for adult human treatment may contain from ; - 0.1 to 1,000 rug, preferably from 1 to 200 mg of ; 26JUN)987£jj 25 active ingredient. The daily dosage will vary \ A - c. ' v • v depending on the product employed but will generally be in the range 1 to 1,000 mg per day for oral administration for adult human treatment. jording to a yet still further aspect of 30 the presentiTTvexjtion there is provided a method of treatment of thehtHa4n or animal body to combat allergy therein, which met^io&--CQmprises administering to the said body an effective amounts^©4a compound of formula I or a physiologically acceptab"t&»-^lt 35 thereof . ...... Certain compounds of formula II used as starting materials for the preparation of the compounds s ( - 9 - of formula I are known compounds being described by for example S.N. Sawhney et al in Ind. J. Chem. I6B/ 605 (1978) , and in fiepmflw Offcnlogungooohriffc 3015150i US Patent No. 3656958 and European Patent Application Publication No. 17543A. However certain compounds of formula II are novel. novl In a further aspect, the invention provides compounds of formula II -N © -n h- (ii) :or. o 10 (wherein R, 15 20 and Rj are as defined above with represents a hydroxy group the moiety R-jRC^ represents other than a group of formula CH3CHC or^CHj the provisos that where R-, * ✓ L •v uk and Xhat where • represents an ethoxygroup the moietyN^RC^, wh^ch represents other than a methylene group) are useful as intermediates in the preparation of compounds of formula I. The compounds of formula II wherein R and R3 represent hydrogen atoms which are not known from the literature may be prepared from p-nitrophenyl-acetic acid according to the following reaction scheme: /-v 26 JUN1987£« /' \. > / - 10 - (wherein R^* is a C^_6 alkoxy group) Compounds of formula II which are not known from the literature may also be prepared from a-phenyl aldehydes by the following reaction scheme: - 11 2 \ \ l q 4 (wherein Rj* is a C1-6 alkoxy group) Where compounds in which R and R^ are C^_ 6 alkyl groups are to be prepared, it is preferable 5 to prepare the intermediate of formula V in the above reaction scheme by the alkylation of an intermediate of formula VI (VI) (wherein R is a C1_g alkyl group and R^* is a alkoxy group) 10 K H yJr-HQ, COR, ' using for example an alkyl iodide R^I and a base such *• i i 1 (J 4 - 12 - as lithium diisopropylamide or lithium N-isopropylcyclo-hexylamide in a suitable solvent such as tetrahydrofuran. The preparation of the intermediates of formula VI themselves is described further below. 5 The compounds of formula II wherein the moiety R^RC^ represents a group of formula CH3Cb£ may in an alternative process be prepared from a-phenyl-propionic acid by the following reaction scheme: H2/Pd ► NH (wherein R^ is a Cj^g alkoxy group) 10 The compounds of formula II wherein (or R) represents a hydrogen atom may also be prepared from l-chloro-4-nitrobenzene by the following reaction scheme (the early stages of which are developed from the reaction scheme discussed by K. Hino et 15 al. in J. Med. Chem. 26, 222-226 (1983)): CI H -0~ 1) NaH/DMSO or DMF 2) RCH(C02C2H5>2 CO-.H R h-|0~nh: C°2C2H5 (not isolated) 1) Na0H/H20/C2H50H 2) HC1 CHjCOOH KSCN Br, COR, K h-K>°= COR1 ' (VI) C2H5OH H V NH. COR. (wherein R is a hydrogen atom or a C^_g alkyl group, preferably a methyl or ethyl group, and R1 is a C1-6 alkoxy group). The following non-limiting Examples illustrate the present invention. In these Examples, temperatures are given in °C and percentages are by weight unless otherwise indicated. - 14 Example 1 : Ethyl 2-oxo-2H-pyrimido [2,1-bl benzothiazole-8-acetate A stirred mixture of ethyl 2-aminobenzothiazole-6-acetate (5 g), methyl propiolate (1.95 g) , and 5 ethanol (30 ml) was heated under reflux for 2 hr. The mixture was allowed to cool and the crude product was collected and then recrystallised from n-butyl alcohol giving the ethyl 2-oxo-2H-pyrimido 12,1-b]benzoth iazole-8-acetate as yellow needles (2.88 g, 48% 10 yield). The ethyl 2-aminobenzothiazole-6-acetate used as starting material can be prepared according to S. N. Sawhney et al., Ind J. Chem. 16B, 605 (1978) . 15 Example 2 : Ethyl 2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-g-methylacetate Using a method similar to that used in Example 1, but starting from the corresponding compound of formula II in which R represents a methyl group 20 (ethyl 2-amino~a-methylbenzothiazole-6-acetate) and from methyl propiolate under reflux for 17 hours, the ethyl 2-oxo-2H-pyrimido [2,1-b]benzothiazole-8-a-methylacetate was prepared (yield 42%). The ethyl 2-amino g-methylbenzothiazole-6-25 acetate used as starting material was prepared as indicated below: Step A : 2-amino-a-methyl benzothiazole-6-acetonitrile. Bromine (27.4 g) in 95% v/v acetic acid (87.5 ml) was added dropwise to a stirred mixture of 2-(g-30 aminophenyl) propionitrile (25 g) (see for example British Patent Mo. 1198212), potassium thiocyanate (66.8 g), and 95% v/v acetic acid (300 ml) at ambient temperature. The mixture was then kept stirring at 50dC for a further 2 hr. before being poured 35 into water (1.5 litres). The solution obtained was filtered through celite and sodium hydrogen carbonate was then added to the filtrate until 4i- . ■ 7 ■■ ' " • t; 0 - 15 - no further precipitation occurred. The precipitate was collected and recrystallised from methanol/water to give the title product as yellow prisms (19.4 g, 56%) M.pt. 165.1°C. 5 IR 3400, 3280 (NH-), 2220 (CN) , 1640, 1540, max • & 1460 and 815 cm" Analysis Calculated %C 59.09; %H 4.46; %N 20.67; %S 15.77 Pound %C 58.76; %H 4.42; %N 20.74; %S 15.7 4 10 for C1qH9N3S. Step B : Ethyl 2-amino-a-raethylbenzothiazole-6-acetate. A stirred solution of 95% ethanol (10 ml), conc. H2S04 (10 g), and the compound of step A 15 above (0.5 g) was heated under reflux for 20 hr. The mixture was then cooled, diluted with water and the ethanol was evaporated off. The resulting solution was neutralised with sodium hydrogen carbonate to give a solid which was collected and recrystallised 20 from methanol/water to give the title product as off-white needles (0.38 g, 61%). M.pt. 146°C IRmax 3370' 3120' 2980, 1710 (ester CO), 1640, 1540, 1470, 1375, 1330, 1295, and 1225 cm"1 25 Analysis - Calculated %C 57.60; %H 5.65: %N 11.20; %S 12.80 Found %C 57.65; %H 5.65; %N 11.20; %S 12.95. for ci2H14N2°2S* The ethyl 2-amino g-methylbenzothiazole-6- 30 acetate used as starting material can also be prepared as indicated below. Ethyl 2-(£-aminophenyl) propionate (154.6 g) (see Arzneim. Forsch, 23, 1090 (1973)) was dissolved in 95% acetic acid and potassium isothiocyanate 35 (261 g) was added with stirring. A solution of Br2 (149.4 g) in 95% acetic acid (750 ml) was then added dropwise at 18-25°C over 2hrs. The mixture - 16 - • was stirred for an extra half hour, then poured into water (8 litres), filtered through celite and then neutralised to pH 5-6 using 20% NajCOj solution (6+ litres) . The product was then extracted 5 into CHjClj and the organic layer was separated, washed with water, dried over MgSO^ and finally filtered and evaporated down. The crude product was then dissolved in hot ethyl acetate (300 ml) and an equal volume of petroleum ether (40-60°) 10 was added. On cooling, cream coloured crystals were formed which were filtered off, washed with ethyl acetate/petroleum ether and dried giving the product 97 g (48.5% yield), m.pt. 146°C A second crop of 29 g was obtained from the mother 15 liquors. Total yield 63%. Example 3 : Ethyl 2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate A stirred mixture of ethyl 2-aminobenzothiazole-6-acetate (5 g) and ethyl phenylpropiolate (6 g) 20 was heated at 200aC in an oil bath for 1 hour. The crude mixture was then purified on a column (200 g Silica) using CHCl^ as eluant. The product obtained was highly coloured and was crystallised from CHCl^ and recrystallised from ethanol giving 25 ethyl 2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate as orange plates (1.99 g, 26% yield). Example 4 : Methyl 2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate Using a method similar to that used in Example 30 1, but starting from the corresponding compound of formula II in which R^' represents a methoxy group and from ethyl phenylpropiolate (compound of formula III) the desired compound was obtained. Example 5 : n-Propyl 2-oxo-4-phenyl-2H-pyr imido 35 [2,1-b] benzothiazole-8-acetate Using a method similar to that used in Example 3, but starting from the corresponding compound 17 - T ^ * of formula II in which R1' represents a n-propoxy group and from ethyl phenylpropiolate (compound of formula III) , the desired compound was obtained. Example 6 : Isopropyl 2-oxo-4-phenyl-2H-pyr imido 5 f2,l-bl benzothiazole-8-acetate Using a method similar to that used in Example 3, but starting from the corresponding compound of formula II in which R^' represents an isopropoxy group and from ethyl phenylpropiolate (compound 10 of formula III), the desired compound was obtained. Example 7 : n-Butyl 2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate Using a method similar to that used in Example 3, but starting from the corresponding compound 15 of formula II in which R^• represents a n-butoxy group and from ethyl phenylpropiolate (compound of formula III), the desired compound was obtained. Example 8 : 2-Oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetic acid 20 A stirred mixture of the ethyl-2-oxo-4-phenyl- 2H-pyrimido [2,1-b]benzothiazole-8-acetate (of Example 3, 2.47 g), methanol (100 ml), and aqueous potassium carbonate solution (2.47 g in 20 ml) was kept at ambient temperature overnight. The 25 methanol was evaporated, the remainder diluted with water, then acidified with concentrated HC1. The precipitate was collected, dried, then recrystallised twice from methanol to give the 2-oxo-4-phenyl-2H-pyriraido [2,1-b] benzothiazole-8-acetic acid 30 as yellow plates (1.72 g, 75% yield). Examples 9 to 19 Using methods similar to that used in Example 3, but starting from ethyl 2-aminobenzothiazole-6-acetate of formula II and from the compounds 35 of formula III in which R£ has the meanings indicated in Table I below and R^ represents an ethyl group, the following compounds were prepared: J 4 - 18 - Example 9 : Ethyl 4-(4-methoxyphenyl)-2-oxo-2H-pyrimido (2,1-b) benzothiazole-8-acetate. Example 10 : Ethyl 4-(4-nitrophenyl)-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate. 5 Example 11 : Ethyl 4-(4-chlorophenyl)-2-oxo-2H-pyriraido 12,1-b] benzothiazole-8-acetate. Example 12 : Ethyl 4-(2-chlorophenyl)-2-oxo-2H-pyrimido (2,1-b] benzothiazole-8-acetate. Example 13 : Ethyl 4-(4-methylphenyl)-2-oxo-2H-10 pyrimido [2,1-b] benzothiazole-8-acetate. Example 14 : Ethyl 4-(3-chlorophenyl)-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate. Example 15 : Ethyl 4-methyl-2-oxo-2H-pyrimido C2,l-bJ benzothiazole-8-acetate. 15 Example 16 : Ethyl 4-ethyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate. Example 17 : Ethyl 2-oxo-4n-propyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate. Example 18 : Ethyl 4-n-butyl-2-oxo-2H-pyrimido 20 [2,1-b] benzothiazole-8-acetate. Example 19 : Ethyl 4-methoxycarbonyl-2-oxo-2H-pyrimido [2,1-b]benzothiazole-8-acetate. Example 20 : Ethyl g-methyl-2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate 25 A mixture of ethyl 2-amino-a-methylbenzothiazole- 6-acetate (50 g) and ethyl phenylpropiolate (34.9 g) was heated with stirring in an oil bath at 100°C for 20 hours, after which time a further 7 g of ethyl phenylpropiolate was added. Heating was 30 continued for a further 96 hours and HPLC then showed the reaction to be 93% completed. Ether (500ml) was then added cautiously and the mixture was stirred under reflux for 2 hours. Seeds of ethyl a-methyl-2-oxo-4-phenyl-2H-pyrimido [2,1-b] 35 benzothiazole-8-acetate were added and the solution was cooled. The crystalline product so obtained was filtered off and washed with ether, then dried, */ f '■* 1f & r* ' f ' ?» - 19 - giving ethyl a-methyl-2-oxo-4-phenyl-2H-pyrimido (2,1-b) benzothiazole-6-acetate (39 g, 51% yield), 99.9% pure HPLC, m.pt. 127-31°C. The ethyl 2-amino-g-methylbenzothiazole-6-5 acetate was prepared as indicated in the preparation of Example 2. Example 21 : g-Methyl-2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetic acid Using a method similar to that used in Example 10 8, but starting from the ethyl g-methyl-2-oxo-4-phenyl-2H-pyrimido [2,1-b) benzothiazole-8-acetate of Example 20, the desired compound was obtained. Examples 22 to 24 Using methods similar to that used in Example 15 20, but starting from ethyl 2-amino-g-methylbenzothiazole-6-acetate and from the compounds of formula III in which Rj has the meanings indicated in Table I below and R4 represents an ethyl radical, the following compounds were prepared. 20 Example 22 : Ethyl g-methyl 4-(4-chlorophenyl) 2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate Example 23 : Ethyl g-methyl 4-(3-chlorophenyl) 2-oxo-2H-pyrimido [2,1-b] benzothiazole-8- acetate Example 24 : Ethyl g-methyl-2-oxo-4n-propyl-2H-25 pyrimido [2,1-b] benzothiazole-8-acetate Example 25 to 43 Using methods similar to those described above and starting from approprate compounds of formulae II and III, the following compounds were 30 prepared: Example 25: Ethyl 4-isopropyl-2-oxo-2H-pyrimido[2,1-b]-benzothiazole-8-acetate. Example 26: Ethyl 4-benzyl-2-oxo-2H-pyrimido[2,1-b]-benzothiazole-8-acetate. 35 Example 27: Ethyl o-methyl-4-benzyl-2-oxo-2H-pyrimido-[2,1-b)benzothiazole-8-acetate. 20 Example 28: Ethyl a-methyl-4-isopropyl-2-oxo-2H-pyr imido[2,1-b]benzoth iazole-8-acetate. Example 29: Ethyl ot-ethyl-4-phenyl-2-oxo-2H-pyrimido-[2,1-b]benzothiazole-8-acetate. 5 Example 30: Ethyl 4-cyclohexyl-2-oxo-2H-pyrimidof2,1-b] -benzothiazole-8-acetate. Example 31: Ethyl a-methyl-4-cyclohexyl-2-oxo-2H-pyr imido[2,1-b]benzothiazole-8-acetate. Example 32: Ethyl a-propyl-4-phenyl-2-oxo-2H-pyrimido-10 [2,1-b]benzothiazole-8-acetate. Example 33: Ethyl a-isopropyl-4-phenyl-2-oxo-2H-pyrimido[2,1-b]benzoth iazole-8-acetate. Example 34: Ethyl a-butyl-4-phenyl-2-oxo-2H-pyrimido-[2,1-b]benzothiazole-8-acetate. 15 Example 35: Isopropyl a-methyl-4-phenyl-2-oxo-2H-pyr imido[2,1-b]benzoth iazole-8-acetate. Example 36: Ethyl a,a-dimethyl-4-phenyl-2-oxo-2H-pyr imido[2,1-b]benzoth iazole-8-acetate. Example 37: Ethyl a-ethyl-a-methyl-4-phenyl-2-20 oxo-2H-pyrimido[2,1-b]benzothiazole-8-acetate. Example 38: Ethyl a-methyl-a-propyl-4-phenyl-2-oxo-2H-pyrimido[2,1-b]benzoth iazole-8-acetate. Example 39: t-Butyl a-methyl-4-phenyl-2-oxo-2H-pyrimido[2,1-b]benzothiazole-8-acetate. 25 Example 40: Ethyl ot/a-diethyl-4-phenyl-2-oxo-2H-pyr imido[2,1-b]benzothiazole-8-acetate. Example 41: Ethyl a-ethyl-a-propyl-4-phenyl-2-oxo-2H-pyrimido[2,1-b]benzothiazole-8-acetate. Example 42: Ethyl a-butyl-a-methyl-4-phenyl-2-30 oxo-2H-pyrimido[2,1-b]benzoth iazole-8-acetate. Example 43: 2,2-Dimethylpropyl a-methyl-4-phenyl-2-oxo-2H-pyr imido[2,1-b]benzoth iazole-8-acetate. Example 44: N,N-Dimethyl-2-oxo-4-phenvl-2H-pyrimido-12,1-b]benzoth iazole-8-acetamide 35 3 g of 2-Oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetic acid was dissolved in tetrahydrofuran (40 ml) and 1,1'-carbonyldiimidazole (2 g) was added. The mixture was stirred at room temperture for 1 2j?*04 hour until dissolution took place. Excess dimethylamine (30% in EtOH) was added and the mixture was stirred for a further 40 minutes. The THF was then removed under vacuo and the residue was taken up in dichloromethane 5 and washed with water# bicarbonate solution, water then dried (MgS04) , filtered and evaporated down. A pale buff solid was obtained which was purified by flash chromatography on silica. Yield 1.1 g, melting point 238-40°C. 10 Examples 45 to 48 Using methods similar to those described above but using the appropriate amine starting material, the following compounds were prepared: Example 45: N-Ethyl-2-oxo-4-phenyl-2H-pyrimido[2,1-b]-15 benzothiazole-8-acetamide. Example 46: 1-(N-Morpholino)-2-(2-oxo-4~phenyl-2H-pyr imido(2,1-b]benzothiazol-8-yl)ethanone. Example 47: N,N-Diethyl-2-oxo-4-phenyl-2H-pyrimido-[2,1-b]benzothiazole-8-acetamide. 20 Example 48: 1-(N-Piperidino)-2-(2-oxo-4-phenyl-2H-pyr imido[2,1-b]benzothiazol-8-yl)ethanone. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 - 22 -TABLE 1 211104 R Rl R2 R3 M.pt.'C H EtO H H 276 Me EtO H H 129 H EtO Ph H 206 H MeO Ph H 225-6 H nPrO Ph H 133.5- H 134.5 H isoPrO Ph H 171.5-172.5 H nBuO Ph H 136-7 H HO Ph H slight decompos. 136°C m.256°C H EtO g-MeOPh H 152 H EtO £-N02Ph H 246 H EtO g-ClPh H 220 H EtO o-ClPh H 196.5 H EtO £-MePh H 183-4 H EtO ra-ClPh H 176-9 H EtO Me H 251-3 H EtO Et H 166.7 H EtO nPr H 158-60 H EtO nBu H 149.6 H EtO CO-Me H 163 Me EtO Ph H 127-31 Me HO Ph H 239-46 Me EtO £-ClPh H 190-1 Me EtO m-ClPh H 76-9 Me EtO nPr H 125-6 211104 TABLE 1 (Continued) Example R R1 R2 R3 M.pt. #( 25 H EtO isoPr H 170-2 0 26 H EtO CHjPh H 197-9 27 Me EtO CH2Ph H 99-101 28 Me EtO isoPr H 149-51 29 Et EtO Ph H 143-5 30 H EtO cyclohexyl H 169-71 31 Me EtO cyclohexyl H 148-50 32 nPr EtO Ph H 131-3 33 isoPr EtO Ph H 126-8 34 Bu EtO Ph H 92-94 35 Me isoPrO i Ph H 153-5 36 Me EtO Ph Me 133-5 37 Me EtO Ph Et 159-61 38 Me EtO Ph Pr 174-6 39 Me t-BuO Ph H 122-5 40 Et EtO Ph Et 138-40 41 Et EtO Ph Pr 163—4 42 Me EtO Ph Bu 143-4 43 Me t-BuCBjC t Ph B 122-3 44 B Me2N Ph B 238-40 45 B EtHN Ph B 210-2 46 B 0' V \—J Ph B 214-6 47 B Et2N Ph H 147-9 48 H o Ph H 190-1 TABLE 1 (Continued) CALCULATED * Example Formula %C %H N% S% 1 C14H12N2°3S 58.3 4.2 9.7 11.1 2 C15H14N2°3S 59.6 4.65 9.25 10.6 3 C20H16N2°3S 65.9 4.4 7.7 8.8 4 - - - - - 5 C21H18N2°3S 66.65 4.8 7.4 8.45 6 C21H18N2°3S 66.65 4.8 7.4 8.45 7 C22H19N2°3S 67.35 5.15 7.15 8.15 8 C18H12N2°3S 64.25 3.6 8.35 9.55 9 C21H18N2°4S 63.95 4.6 7.1 8.15 10 C20H15N3°5S 58.65 3.7 10.25 7.85 11 C20H15N2°3C1S 60.2 3.8 7.0 8.05 12 C20H15N2°3C1S 60.2 3.8 7.0 8.05 13 C21H18N2°3S 66.65 4.8 7.4 8.45 14 C20tt15N2°3C1S 60.2 3.8 7.0 8.05 15 C15H14N2°3S 59.6 4.65 9.25 10.6 16 C16H16N2°3S 60.75 5.1 8.85 10.15 17 C17H18N2°3S 61.8 5.5 8.5 9.7 18 C18H20N2°3S 62. 75 5.85 8.15 9.3 19 C16H14N2°5S 55.5 4.05 8.1 9.25 20 C21H18N2°3S 66.65 4.8 7.4 8.45 21 C19H14N2°3S 66.15 4.05 8.0 9.15 22 C21H17N2°3C1S 61.1 4.15 6.8 7.75 23 C21H17N2°3C1S 61.1 4.15 6.8 7.75 24 C18H20N2°3S 62.75 5.85 8.15 9.3 * ANALYSES (to nearest 0.05%) - 25 -TABLE 1 (Continued) CALCULATED * Example Formula %C %H N% S% 25 C17H18N2°3S 61. 80 5. 49 8.48 9. 70 26 C21H18N2°3S 66. 65 4. 79 7.40 8. 47 27 C22H20N2°3S*1/2H2° 65. 82 5. 27 6.98 7. 99 28 C18H20N2°3S 62. 77 5. 85 8.13 9. 29 29 C22H20N2°3S 67. 33 5. 14 7.14 8. 17 30 C20H22N2°3S 64 . 84 5. 99 7.56 8. 65 31 C21H24N2°3S 65. 60 6. 29 7.28 8. 34 32 C23H22N2°3S 67. 96 5. 46 6.89 7. 89 33 C23H22N2°3S'1/2H2° 66. 49 5. 58 6.74 7. 72 34 C24H24N2°3S 68. 55 5. 75 6.66 7. 62 35 C22H20N2°3S 67. 33 5. 14 7.14 8. 17 36 C22H20N2°3S 67. 33 5. 14 7.14 8. 17 37 C23H22N2°3S 67. 96 5. 46 6.89 7. 89 38 C24H24N2°3S 68. 55 5. 75 6.66 7. 62 39 C23H22N2°3S 67. 96 5. 46 6.89 7. 89 40 C24H24N2°3S 68. 55 5. 75 6.66 7. 62 41 C25H26N2°3S 69. 10 6. 03 6.45 7. 38 42 C25H26N2°3S 69. 10 6. 03 6.45 7. 38 43 C24H24N2°3S 68. 55 5. 75 6.66 7. 62 44 ^20^17^3^2^* J-/2®2*^ 64. 50 4. 87 11.28 8. 61 45 C20H17N3°2S*1/2H2° 64. 50 4. 87 11.28 8. 61 46 c:l2Hl 9Na°3.s* 1/2H-?° 63. 75 4. 86 10.14 7. 73 47 C22®21N3°2S 67. 50 5. 41 10.73 8. 19 48 C23H21N3°2S 68. 45 5. 25 10.41 7. 95 * ANALYSES (to nearest 0.05%) i TABLE 1 (Continued) FOUND * Example %C %H %N %S 1 58.25 4.25 9.75 11.1 2 59.5 4.65 9.3 10.45 3 A 66.2 4.5 7.65 8.85 % 5 66.55 4.85 7.35 8.35 6 66.65 4.85 7.4 8.45 7 67.35 5.15 7.2 8.2 8 64.25 3.65 8.3 9.55 9 64.05 4.65 7.1 8.2 10 58.6 3.75 10.25 7.8 11 60.15 3.85 6.95 8.05 12 60.25 3.9 7.0 8.1 13 66.45 4.85 7.40 8.6 14 60.25 3.9 7.05 8.1 15 59.6 4.7 9.3 10.55 16 60.5 5.1 8.8 10.15 17 61.7 5.5 8.45 9.75 18 62.5 5.9 8.15 9.45 19 55.3 4.15 8.0 9.15 20 66.5 4.85 7.45 8.4 21 64.9 4.05 8.0 9.1 22 61.1 4.25 6.75 7.75 23 60.85 4.3 6.75 7.85 24 62.65 5.85 8.15 9.3 * ANALYSES (to nearest 0.05%) - 27 -TABLE 1 (Continued) FOUND * Example %C %H %N %S 25 61.88 5.51 8. 51 9.64 26 66.55 4.85 7. 37 8.43 27 65.94 5.34 6.88 8.02 28 62. 73 5.93 8.11 9.17 29 67.43 5.16 7.14 8.12 30 64.85 5.95 7.62 8.64 31 65.62 6.34 7.21 8. 35 32 67.84 5.54 6.85 7.75 33 66.56 5.59 6.61 7.65 34 68.35 5.83 6.62 7.72 35 67.27 5.20 7.08 7.97 36 67.42 5.16 7.09 8.22 37 67.66 5.66 6.67 7.59 38 68.30 5.86 6.54 7.53 39 68.10 5.50 6.84 7.87 40 68.47 5.85 6.58 7.61 41 69.08 6.14 6.34 7.37 42 68.91 6.14 6.32 7.28 43 68.62 5.78 6.66 7.63 44 64.50 4.72 11.18 8.54 45 64.46 4. 71 11.28 8.62 46 63.86 4.76 10.00 7.75 47 67 .20 5.40 10.58 8.17 48 68.19 5.31 10.26 7.95 * ANALYSES (to nearest 0.05%) 2 II t 04 - 28 - Example 49 Tablets were prepared according to the formulation: - compound of Example 3 15 mg ; - excipient g. s. for one one tablet up to....100 mg. (Details of the excipient : lactose, starch, talc, magnesium stearate). Example 50 A dosed aerosol was prepared delivering per dose: - compound of Example 20 2 mg ? - emulsifier 0.15 mg ; - propellant 50 mg. Example 51 Tablets were prepared according to the formulation: - compound of Example 20 15 mg ; - excipient q. s. for one tablet up to 100 mg. (Details of the excipient : lactose, starch, talc# magnesium stearate) PHARMACOLOGICAL ACTIVITY Test : Antigen induced elevation of lung perfusion pressure Animals Male Dunkin Hartley guinea pigs (Porcellus, 450-700g) are used (four per drug concentration) housed in cages. Animals are sensitised by two weekly exposures to aerosol ovalbumen (1% W/V). Drugs Animals are anaesthetised with 2.5 mg/kg diazepam i. p. and 1 ml/kg Hypnorm i.m. Method Following anaesthesia, the animals are exsanguinated by severing both carotid arteries. The chest is opened and the lungs removed, split into two at the carina and both cannulated via the main lobar bronchus and connected to a perfusion system. ... * i U 4 - 29 - Lungs were perfused with aerated krebs fluid (95% 0^ : 5% COj) at 37°C. Ovalbumen (5/ig in 0.1ml) was injected through an injection port proximal to each lung. Elevation of perfusion pressure 5 by the antigen is recorded. Sixty minutes later, 15 ^ig ovalbumen is administered. Research compounds are added to the krebs fluid reservior, thirty minutes prior to the second antigen dose. For each weekly batch of animals used, control measurements 10 are made without drug treatment (n=10). The second antigen response is expressed as a percentage of the first. For drug treatments at least four lungs (from four different animals) are used per concentration. Percentage inhibition 15 of antigen induced bronchoconstriction is calculated. (IC50uM). Results are given in Table 2 below. ) TABLE 2 Product of Example *^50 uM 2 >100 3 1 4 10 5 <10 6 o H 1 H 7 > 10 9 1 10 10-100 11 10 12 H 1 H • O 13 -c 1 14 £1 15 10-100 16 100 17 1-10 18 10 20 0. 22 0.1-1 23 < 1 24 >10 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> I 2 111 - 31 - TABLE 2 (Continued) Product of Example IC50 uM 25 10-100 27 10-100 28 10-100 29 0.1 30 o H 1 rA 31 10 32 1 33 10-100 34 1-10 35 0.1-1 36 1 O 37 1 38 l 39 0.1 40 10-100 41 10-100 42 10-100 43 0.1 44 10-ICO 45 10-100 46 >100 47 10 48 10-100 > / f v WHAT 4fWE CLAIM IS:- ' 1. Compounds of formula T 32 R 2 R 3 1 0 (I) (wherein R and R^, which may be the same or different, 5 each represents a hydrogen atom or a straight or branched C^_g alkyl group or together with the intervening carbon atom represent a C^_g cycloalkyl group; R^ represents a hydroxy group, a straight or branched C^_g alkoxy group or a group of formula (wherein R^ and Rg, which may be the same or different, each represents a hydrogen atom or a C^_g alkyl 15 group or together with the intervening nitrogen atom represent a piperidino or roorpholino group); and R2 represents a hydrogen atom, a straight or branched C^_g alkyl group, a C2_^ alkoxycarbonyl group, a C^_g cycloalkyl group, an aralkyl group, 20 an aryl group (unsubstituted or substituted by one or more halogen atoms or C^_g alkyl, C^_g alkoxy or nitro groups), or a heteroaryl group] and salts thereof. 2. Compounds as claimed in claim 1 wherein R 25 and R^, which may be the same or different, each represents a hydrogen atom or a methyl or ethyl 10 (A) J i chain or branched C^_g alkyl group, a mebhoxycarbonyl 5 group or a phenyl group optionally substituted by one or more halogen atoms or methyl, methoxy or nitro groups. thiazole-8-acetate; ethyl 2-oxo-4-(p-methoxyphenyl)-2H-pyrimido[2,1-b]-benzothiazole-8-acetate; ethyl 2-oxo-4-(o-chlorophenyl)-2H-pyrimido[2,1-b]-15 benzothiazole-8-acetate; ethyl a-methyl-2-oxo-4-phenyl-2H-pyrimido[2,1-b] benzoth i azole-8-acetate; ethyl a-methyl-2-oxo-4-(p-chlorophenyl)-2H-pyr imido[2,1-b] benzothiazole-8-acetatey and 20 ethyl a-ethyl-2-oxo-4-phenyl-2H-pyrimido[2f1-b] benzothiazole-8-acetate; and salts thereof. 5. Compounds as claimed in claim 1 as herein specifically disclosed in any one of the Examples. 25 6. A process for the preparation of compounds as claimed in claim 1 wherein represents a hydroxy or alkoxy group which comprises reacting a compound of formula II 10 4. Compounds as claimed in claim 1 selected from ethyl 2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzo- N .N H '2 (II) R 3 1 COR, * 30 (wherein R and are as defined in claim 1 and represents a hydroxy group or a C^_g alkoxy - 34 - group) with a compound of formula III R2-C=C-C02R4 (III) (wherein R2 is as defined in claim 1 and R^ represents an alkyl group, followed, if desired, by the isolation 5 of, and/or formation of a salt of, the compound of formula I thus obtained. 7. A process as claimed in claim 6 for the preparation of compounds as claimed in claim 1 wherein R2 represents a hydrogen atom wherein the reaction is effected 10 under reflux in a solvent in the presence of a catalyst. 8. A process as claimed in claim 6 for the preparation of compounds as claimed in claim 1 wherein R2 is other than a hydrogen atom wherein the reaction 15 is effected by heating together the compounds of formula II and III in the absence of a solvent. 9. A process for the preparation of compounds as claimed in claim 1 wherein R^ represents a C^_g alkoxy group which comprises reacting a compound 20 as claimed in claim 1 wherein R^ represents a hydroxy group with an alcohol of formula HO-Rj (IV) (wherein R£ represents a C^_g alkyl group). 10. A process for the preparation of compounds 25 as claimed in claim 1 wherein R^ represents a C^_g alkoxy group which comprises transesterifying a v£> compound of formula I wherein R^ represents a different C^_g alkoxy group. 11. A process for the preparation of compounds 30 as claimed in claim 1 wherein R^ represents a hydroxy group which comprises deesterifying a compound as claimed in claim 1 wherein R^ represents a C^_g - 35 - alkoxy group. 12. A process as claimed in claim 11 wherein deesterification is effected by means of potassium carbonate. 13. A process for the preparation of compounds as claimed in claim 1 wherein represents a group of formula (A) as defined in claim 1 which comprises reacting a compound of formula 1 in which R^ represents a hydroxy group with a compound of formula 10 /B5 ' (B) R6 (wherein R^ and Rg are as defined in claim 1) in the presence of 1,1'-carbonyldiimidazole• 15 14. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of the Examples. 15. Compounds as claimed in claim 1 whenever prepared by a process as claimed in any one of 20 claims 6 to 14. 16. Pharmaceutical compositions comprising as active ingredient a compound of formula I as defined in claim 1 or a physiologically acceptable salt thereof in association with a pharmaceutica 1 carrier c- vErw -25 and/or excipient. f'7 -4 17. Composition as claimed in claim 16 in the (t*26JUN 7^/i form of dosage units, each dosage unit containing V\ *!•/ \ v\ / from 0.1 to 1000 mg of active ingredient. \*V t.*?/ 18. Compositions as claimed in claim 17 wherein 30 each dosage unit contains from 1 to 200 rag of active ingredient. 19. Pharmaceutical compositions substantially as herein described in any one of the Examples. 20. Compounds of formula I as defined in claim 35 1 and physiologically acceptable salts thereof suitable for use in therapy. BALOVVil-J, SOU CAR'iV </div>