CA1286290C - Anti-allergic pyrimido[2,1-l-b]benzothiazoles - Google Patents
Anti-allergic pyrimido[2,1-l-b]benzothiazolesInfo
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- CA1286290C CA1286290C CA000514995A CA514995A CA1286290C CA 1286290 C CA1286290 C CA 1286290C CA 000514995 A CA000514995 A CA 000514995A CA 514995 A CA514995 A CA 514995A CA 1286290 C CA1286290 C CA 1286290C
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/26—Radicals substituted by sulfur atoms
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Abstract
ABSTRACT OF THE DISCLOSURE:
This invention is concerned with novel pyrimido-/
2,1-b/ benzothiazoles of formula I
This invention is concerned with novel pyrimido-/
2,1-b/ benzothiazoles of formula I
Description
\
lZ~3~iZ~
The present invention relates to a process for preparing novel pyrimido-/2,1-b/ benzothiazoles and their pharmaceutically acceptable salts.
The invention also relates to these novel pyrimi-do~2,1-b~ benzothiazoles and to their pharmaceutically accep-table salts, which have been found to possess interesting pharmacological properties, in particular antiallergic activities.
The novel pyrimido/2,1-b/benzothiazoles according to the invention are of formula I
lS U R ~ ~ (I) wherein R and R3, which may be the same or different, each represents a hydrogen atom or a straight-chained or branched Cl 6 alkyl group or together with the intervening carbon atom represent a C3 6 cycloalkyl group; Rl represents a C7 12 straight-chained, branched or cyclic alkoxy group; and R2 represents a hydrogen atom, a straight-chained or branched Cl 6 alkyl group, a C2 7 alkoxycarbonyl group, a C3 6 cyclo-alkyl group, an aralkyl group, an aryl group (unsubstituted or substituted by one or more halogen atoms or Cl 6 alkyl, Cl 6 alkoxy or nitro groups) or a heteroaryl group.
In respect of formula I above, where straight-chained or branchled Cl 6 alkyl groups are referred ~L28~
to, these may, for example, be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl or hexyl groups.
C3 6 cycloalkyl groups may, for example, be cyclohexyl groups.
C7 12 straight-chained, branched or cyclic alkoxy groups may, for example, be heptyloxy, octyloxy, nonyloxy,decyloxy, l-me-thylcyclohexyloxy or l-adamantyloxy groups. Aralkyl groups may, for example, be benzyl groups. Aryl groups may, for example, be C6_12 groups such as phenyl or naphthyl groups.
C2 7 alkoxycarbonyl groups may, for example, be methoxycar-bonyl, ethoxycarbonyl or propoxycarbonyl groups. Where halogen atoms are referred to these may, for example, be chlorine, fluorine or bromine atoms. Where Cl 6 alkoxy groups are referred to, these may, for example, be methoxy, ethoxy, propoxy, butoxy, pentoxy or hexyloxy groups. Hete-roaryl groups may contain one or more hetero, e.g. sulphur, atoms is the aryl ring and may, for example, be 2-thienyl groups.
The compounds of formula I as hereinbefore defined 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, hydriodic, nitric, sulphuric, phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic and aspartic acids, alkanesulphonic acids (e.g. methanesulphonic acid) and arylsulphonic acids (e.g. benzenesulphonic acid).
As examples of the preferred compounds according to the invention, particular reference may be made to those compounds of formula I, and acid addition salts thereof, wherein one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups.
12~
Also as examples of preferred compounds according the invention, ~ention may be made of those compounds of formula I, and acid addition salts thereof, wherein one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups and R2 reprensents a hydroglen atom, a straight-chained or branched Cl 6 alkyl group, a methoxycarbonyl group or a phenyl group optionally substituted by one or more halogen atoms or methyl, methoxy or nitro groups.
As examples of especially preferred compounds accor-ding to the invention,mention may be made of those com-^
pounds of formula I, and acid addition salts thereof, wherein one of both of R and R3 represent hydrogen atoms or methyl or ethyl groups, R2 represents a phenyl group and Rl repre-sents a l-methylcyclohexyloxy or l-adamantyloxy group.
More particularly preferred compounds according to the invention include:
l-methylcyclohexyl ~-methyl-2-oxo-4-phenyl-2H-pyrimid~ ,1-b~benzothiazole-8-acetate;
l-adamantyl a-methyl-2-oxo-4-phenyl-2H-pyrimido-L2,1-b] benzothiazole-8-acetate;
and aci~ addition salts of these compounds.
The process for the preparation of the novel pyrimi-do/2,1-b/benzothiazoles of formula I and their pharmaceuti-cally acceptable acid addition salts according the invention, comprises reacting a compound of formula II
R ~ ~ H2 R3 ~ (II) OR
(wherein R, Rl and R3 are as hereinbefore defined) with a compound of formula III
R2_c_c_.co2R4 (III) . : . . ..
~ Z86~9~
(wherein R2 is as hereinbefore defined and R4 represents an alkyl group, preferably a Cl_3 alkyl group) to give a corresponding compound of formula I which is isolated, and, if desired, salified/or which is transesterified by an alcohol of formula IV
H-R' (IV) (~-herein R'l represents a C7 12 straight chained, branched or cyclic alkoxy group) to aive a correspording compound of formula I wherein R1 has the mearing of R'l, which is isolated and,if desire~,salified.
The above process of the invention is preferably carriea out in the following manner.
The reaction of the 2-aminobenzothiazole of formula II with the propiolate of formula III may be effected under reflux and in the presence of an alcohol such as ethanol and a catalyst such as palladium.
~owever, the reaction is preferably effected under heating, e.g. to 100-180C, and in the absence of a solvent.
Alternatively, the process for the preparation of the compounds of formula I, according of the invention, comprises reacting a compound of formula V
R3R "~'~=
0~ 1 -~L2~36Z90 Iwherein R "l represents a hydroxy group or a Cl 6 alkoxy group) with an alcohol of formula VI
H-Rl (VI) (wherein Rl represents a C7 12 straight-chained, branched or cyclic alkoxy group), to give a corresponding compound of formula I which is isolated and, if desired, salified.
The compounds of formula I obtained from either of the processes described above may subsequently be converted into the acid addition salts thereof, particularly the phy-siologically acceptable acid addition salts thereof with inorganic or organic acids, by any conventional method such as for example by reacting the compounds as bases with a solution of the corresponding acid in a suitable solvent.
Conversely, the acid addition salts of the compounds of for-mula I may, if desired subsequently be converted into com-pounds of formula I.
The compound according to the present invention haveinteresting pharmacological properties. In particular, com-pounds which have been tested exhibit remarkable antiallergic properties. These properties are illustrated by experimental test results given hereinafter. It will be appreciatedtherefore that the compounds according to the invention may be useful in medecine. For pharmaceutical use, it will of course be the case that the acid addition salts of the com-pounds of formula I will be physiologically acceptable. Other acid addition salts may, however, `" ~L2 find use, for example in the preparation of compounds of formula I and their physiologically acceptable acid addition salts.
The compounds of formula I and physiologically acceptable acid addition salts thereof may thus find use in the treatment of allergy in the human or ar.imal body.
Preferred in this connection are compounds of formula I wherein one or both o~ R and R3 represent hydrogen atoms or methyl or ethyl groups and physiolog-ically acceptable acid addition salts of such compounds.
Also preferred are compounds of formula I wherein one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups and R2 represents a hydrogen atom, a straisht-chained or branched Cl ~ alkyl g~oup, a methoxycarbonyl group or a phenyl group optionally substituted by one or more halogen atoms or methyl, nitro or methoxy groups and physiologically acceptable acid addition salts of such compounds. Especially preferred are compounds of formula I wherein one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups, R2 represents a phenyl group and Rl represents a l-methylcyclohexyloxy or l-adamant-yloxy group and physiologically acceptable acid addition salts of such compounds.
Particularly suitable for use as medicaments are the following compounds:
l-methylcyclohexyl ~-methyl-2-oxo-4-phenyl-2~-pyrimido[2,1-b]benzothiazole-8-acetate;
l-adamantyl ~-methyl-2-oxo-4-phenyl-2H-pyrimido-~2,1-b]benzothiazole-8-acetate;
and their physiologically acceptable acid addition salts.
Such compounds may have utility for example in the treatment of allergic asthma and asthmatiform bronchitis o~ allergic origin.
, 86~90 The compounds of formula I and their physiologically acceptable acid addition salts may be used to prepare pharmaceutical compositions containing as active ingredient at least one compound of formula I or a physiologically acceptable acid addition salt thereof in admixture with at least one pharmaceutical carrier and/or excipient.
For pharmaceutical administration, the compounds of formula I and their physiologically acceptable acid addition salts may for example be incorporated in compositions for oral, re~:tal and parenteral (including topical) administration, optionally in conjunction with 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 ~0 capsules, granules, 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 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.
Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units for adult human treatment may contain from 0.1 to 1,000 mg, preferably from 1 to 200 mg, of ac~ive inqredient. The daily dosage will vary depending on the product employed but will generally be in the range 1 to 1,000 mg per day for oral 862~) administration for adult human treatment.
Certain compounds of formula II used as starting materials for the preparation of the compounds of formula I are known compounds being described by, for example, S.N. Sawhney et al. in Ind. J.
Chem., 16~, 605 (1978), and in German Offenlegungsschrift 2,015,158; US Patent No. 3,656,958 and European laid-open Patent Application No. 01,017,543. However certaincompounds of formula II are novel.
- The compounds of formula II wherein R and R3 represent hydroqen atoms which are not known ~5 from the literature may be prepared from p-nitrophenyl-acetic acid according to the following reaction scheme:
~t~ 0~ Pd-C
~ H~S04 ~ H2 COO~ COR1 EtOH CORt AcOH ~ N~
Br2 ~ ~/>--NH2 CORl (wherein Rl is as hereinbefore defined).
Compounds oE formula II which are not known Erom the literature may also he prepared from ~-phenyl aldehydes by the following reaction scheme:
1~8~i290 _ R3~ 3~3 R3~/
_~ ~ 10% Pd-~ ~ NH2 KSCN
H ~ R ~ ~VII) R ~ AeOH~r2_ r R ~ \ ~ NH2 (wherein R, Rl and R3 are as hereinbefore defined).
~ here compounds in which R and R3 are Cl 6 alkyl groups are to be prepared, it is preferable S to prepare the intermediate of formula VII in`the above reaction scheme by the alkylation of an intermediate of formula VIII
H ~ No2 (VIII) CORl (wherein R is a Cl_6 alkyl group and Rl is as hereinbefore defined) using for example an alkyl iodide R3I
and a base such as lithium diisopropylamide or lithium N-isopropylcyclohexylamide in a suitable , .
.. . . , ~ .
- lZ~6290 solvent such as tetrahydrofuran. The preparation of the intermediates of formula V~} themaeLyes ls described ~urther below.
The compounds of formula II wherein the moiety R3RC~ represents a group of formula CH3CH may in an alternative process be prepared from 2-phenyl-propionic acid by the following reaction scheme:
R1-H/HCl ~ HN03 ~ 2 c~ C~
OOH CO~l COR1 ~ C~ ;~, ~ r ORl ~R1 twherein Rl is as hereinbefore defined).
The compounds of formula II wherein R3 (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 al. in J. Med. Chem., 26, 222-226 (1983)]:
128~29l0 ~ 1) Na~/DM~O or DMF ~
Cl ~ 2 ~C~2c- ~ 2 2) RCH~C02C2H~)2 (not lsolated) ~; NaOH/H20/C2~50H
/ 2) HCl R R
Rl-- ~N02 C2H COR1 (VIII) / ~ Pd-C
fr--~ CH3COOH R ~ N
H ~ NH XSCN ~ ~ ~ NH2 CORl COR1 (wherein R is a hydrogen atom or a Cl 6 alkyl group, preferably a methyl or ethyl group, and Rl is as hereinbefore defined).
Alternatively, the compounds of formula ~ 2 CH ¦ ll ,~, CoRl ~2~6290 ~wherein Rl is as hereinbefore defin~ed) may be prepared from 2-~p-nitrophenyl)propionic acid by the following reaction scheme~
CH3 ~ ~ 2 1) SOC12 C
H / COOH 2) Ri H ~ / CO-Rl ~ he compounds of formula V ~7herein R, R2 and R3 are as defined hereinbefore and R"l represents a`hydroxy radical or a Cl 6 alkoxy group may be prepared according to the process described in European ~aid-open Patent Application n 0 153 230.
The following non-limiting Examples are intended to illustrate the present invention. In these Examples, temperatures are given in C and percentages are by weight unless otherwise indicated.
Example 1: 1-MethYlcyclohexyl -methyl-2-oxo-4-phenyl-2H-Pyrimido[2,1-b]benzothiazole-8-acetate Step A: l-Methylcyclohexyl 2-(p-nitrophenyl)propionate.
A stirred mixture of 2-~p-nitrophenyl)propionic acid (97.5 9) [see J. Med. Chem., 26, 222-226 (1983)], thionyl chloride (40 ml) and ~ry toluene (500 ml) was heated at 80C for 5 hours. The mixture was then allowed to cool and the solvent removed under reduced pressure. The residual oil was dissolved in dry toluene (400 ml), and l-methylcyclohexanol (100 9) was then added to the solution. The stirred mixture was heated at 80C for 1 hour and then at ambient temperature overnight. The solution was washed with 5% NaHCO3 solution, then water, dried over MgSO4 and finally evaporated to dryness.
The crude mixture was purified on a column ~600 9 silica) using C'~C13 as the eluant, giving l-methyl-cyclohexyl 2-(p-nitrophenYl)propionate as a golden yellow liquid (34.95 g, 24% yield).
}R vmax (thin film): 2940, 1725 (ester), 1520, 1345 and 1150 cm 1 Step B: l-Methylcyclohexyl~2-(p-aminophenyl)propionate.
A stirred solution of l-methylcyclohexyl 2-(p-nitrophenyl)propionate (34.9 g) in absolute ethanol (250 ml) was hydrogenated at atmospheric pressure in the presence of 10% palladium on carbon catalyst. After the uptake of hydrogen gas was complete, the catalyst was ~iltered off through CELITE~ and the filtrate evaporated to dryness.
Trituration of the residue with petroleum ether gave l-met~ylcYclohexyl 2-(p-aminophenYl)propionate lX8629~
_ 14 _ as creamy white crystals (21.02 9, 6796 yield)O
M.p.: 85-87C.
IR vmax (KBr~: 3640 (-NH2), 3370 (-N~I2), 2940, 1710 and 1215 cm 1, Step C: l-Methylcyclohexyl 2-amino-~-methylbenzothiazole-6-acetate.
A stirred mixture of l-methylcyclohexyl 2-(p-aminophenyl)propionate ~20.9 g) and potassium 10 thiocyanate (31.0 g) in glacial ac~tic acid (150 ml) was heated in an oil bath at 50C and a solution of Br2 (25.6 g) in glacial ac~etic acid (15 ml) was added dropwise over 30 mins. The mixture was stirred at 50C for an extra 30 mins, then cooled and poured 15 into a 3:2 water/ethyl acetate mixture (1,000 ml).
The resulting mixture was neutralised to pH 5-6 using solid NaCO3 and filtered through CELITE
and the orgarlic layer was then separated, washed with water, dried over MgSO,t and finally evaporated 20 to dryness. Trituration of the residual oil with petroleum ether gave l-methYlcYclohexyl 2-amino-c~-methYlbenzothiazole-6-acetate as creamy white crystals (18.62 g, 73Y6 yield).
M.p.: 165-167C.
25 IR vmax (KBr): 3410, 2930, 1710 (ester), 1550 and 1215 cm Step D: l-Methylcyclohexyl a-methyl-2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole-8-acetate.
A stirred mixture of l-methylcyclohexyl 2-amino-~-methylbenzothiazole-6-acetate (3.2 91 and ethyl phenylpropiolate (3.5 9) was heated in an oil bath (160C) for 30 mins during which time a further 3.5 g of ethyl phenylpropiolate was added 35 dropwise. The mixture was then cooled to 60C
and ether (30 ml) was added cautiously. Further cooling gave 1-methYlcyclohexyl c~-methyl-2-oxo-* trade mark ~ r~
~X86X9~3 4-phenYl-2~-Pyrimid-ol2~l-b]benzothiazole-8-acetate as pale yellow crystals ~1.82 g, 41% yield).
M.p.: 168-170C.
IR ~max (~Br): 2930, 1720 (e5ter), 1650, 1510 and S 1145 cm Analysis:
Calculated %C 69 . 93, ~H 5.87, %N 6.27, %S 7.18.
Found %C 69.87, %~ 5.90, ~N 6.23, %s 7.23.
Example 2: l-Adamantyl ~-methYl-2-oxo-4-phenyl-2~-pyrimido[2 r 1-b]benzothiazole-8-acetate Step A: l-Adamantyl 2-(p-nitrophenyl)propionate.
~ sing a method similar to that used in the preparation of l-methylcyclohexyl 2-(p-nitrophenyl)propionate starting from 2-(p-nitrophenyl)propionic acid (14.6 9)~
but using l-adamantanol instead of l-methylcyclohexanol, the desired product was obtained as a light yellow viscous liquid t22.74 9, 92% yield).
IR ~max (thin film): 2920, 1725 (ester), 1520, 1345 and 1055 cm 1.
Step B: l-Adamantyl~ 2-(p-aminophenyl)propionate.
Using a method similar to that used in the preparation of l-methylcyclohexyl 2-(p-aminophenyl)-propionate, but starting from l-adamantyl 2-(p-nitrophenyl)propionate (21.4 9), the title comPound was obtained as a light yellow viscous liquid (19.42 9, 100% yield).
IR ~max (thin film): 3450 (-NH2), 3370 (-NH2), 2910, 172Q (ester) and 1055 cm 1 Step C: l-Adamantyl 2-amino-~-methylbenzothiazole-6-acetate.
Using a method similar to that used in the preparation of l-methylcyclohexyl 2-amino-~-methyl-benzothiazole-6-acetate, but starting from l-adamant-yl 2-(p-aminophenyl)propionate (19.1 g), the ~28~2~3 _ 16 _ title comPound was obtained as a creamy white solid (lB.97 g, 83% yield~.
M.p.: 151-153C.
IR ~max (RBr): 3400, 2910, 1710 (ester), 1540 and 1210 cm~l.
Step D: l-~damantyl ~-methyl-2-oxo-4-phenyl-2R-pyrimido[2,1-b~benzothiazole--8-acetate.
Using a method similar to that used in the preparation of l-methylcyclohexyl ~-methyl-2-oxo-4-phenyl-2~-pyrimidot2,1-b]benzothiazole-8-acetate, but starting from l-adamantyl 2-amino-~-methyl-benzothiazole-6-acetate (8.9 9) and heating at 160C for 1 hour, the title compound was obtained lS as a light yellow solid after recrystallisation from ethyl acetate/petroleum ether (4.73 9, 39%
yiela) .
M.p.: 188-190C.
IR ~max (RBr): 2910, 1720 (ester), 1640, 1510 and 1390 cm 1 Analysis:
Calculated %C 71.88, %H 5.82, %N 5.78, ~S 6.62.
Found %C 71.71, %H 5.87, %N 5.75, %S 6.57.
Example 3 Tablets were prepared according to the formulation:
- compound of Example 1...................... ..15 mg - excipient g.s. for one tablet up to........ .100 mg.
(Details of the excipient : lactose, starch, talc, maynesium stearate).
Example 4 A dosed aerosol was prepared delivering per dose:
- compound of Example 2...................... .2 mg - emulsifier................................ 0.15 mg 35 - propellant................................. 50 mg.
ExamPle 5 Tablets were prepared according to the formulation:
- compound of Example 2..................... ..15 mg - excipient q.s. for one tablet up to ...... 10~ mg.
(Details of the excipient : lactose, starch, talc, magnesium stearate) PHARMACOLOGICAL ACTIVITY
Test : Antiqen induced elevation of lung perfusion 10 Pressure Animals Male Dunkin ~artley guinea pigs (Porcellus, 450-700 g) are used (four per drug concentration) housed in cages. Animals are sensitised by two ~ee~ly exposures to aerosol ovalbumen (1% W/V).
Druqs Animals are anaesthetised with 2.5 mg/kg diazepam i.p. and 1 ml/kg ~ypnorm 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.
Lungs are perfused with aerated krebs fluid (95 2 : 5% CO2) at 37C. Ovalbumen (5~9 in 0.lml) is injected through an injection port proximal to each lung. Elevation of perfusion pressure by the antigen is recorded. Sixty minutes later, 15 pg ovalbumen is administered. Research compounds are added to the krebs fluid reservoir, thirty minutes prior to the second antigen dose. For each weekly batch of animals used, control measurements 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 tfrom four different animals) ~.2~6290 are used per concentration. Percentage inhibition of antigen induced bronchoconstriction is calculated 50 1~) Results are given in Table I below.
Table I
. _ ._ _ Product of Example IC50 ~M
_ __ _ , . .. _
lZ~3~iZ~
The present invention relates to a process for preparing novel pyrimido-/2,1-b/ benzothiazoles and their pharmaceutically acceptable salts.
The invention also relates to these novel pyrimi-do~2,1-b~ benzothiazoles and to their pharmaceutically accep-table salts, which have been found to possess interesting pharmacological properties, in particular antiallergic activities.
The novel pyrimido/2,1-b/benzothiazoles according to the invention are of formula I
lS U R ~ ~ (I) wherein R and R3, which may be the same or different, each represents a hydrogen atom or a straight-chained or branched Cl 6 alkyl group or together with the intervening carbon atom represent a C3 6 cycloalkyl group; Rl represents a C7 12 straight-chained, branched or cyclic alkoxy group; and R2 represents a hydrogen atom, a straight-chained or branched Cl 6 alkyl group, a C2 7 alkoxycarbonyl group, a C3 6 cyclo-alkyl group, an aralkyl group, an aryl group (unsubstituted or substituted by one or more halogen atoms or Cl 6 alkyl, Cl 6 alkoxy or nitro groups) or a heteroaryl group.
In respect of formula I above, where straight-chained or branchled Cl 6 alkyl groups are referred ~L28~
to, these may, for example, be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl or hexyl groups.
C3 6 cycloalkyl groups may, for example, be cyclohexyl groups.
C7 12 straight-chained, branched or cyclic alkoxy groups may, for example, be heptyloxy, octyloxy, nonyloxy,decyloxy, l-me-thylcyclohexyloxy or l-adamantyloxy groups. Aralkyl groups may, for example, be benzyl groups. Aryl groups may, for example, be C6_12 groups such as phenyl or naphthyl groups.
C2 7 alkoxycarbonyl groups may, for example, be methoxycar-bonyl, ethoxycarbonyl or propoxycarbonyl groups. Where halogen atoms are referred to these may, for example, be chlorine, fluorine or bromine atoms. Where Cl 6 alkoxy groups are referred to, these may, for example, be methoxy, ethoxy, propoxy, butoxy, pentoxy or hexyloxy groups. Hete-roaryl groups may contain one or more hetero, e.g. sulphur, atoms is the aryl ring and may, for example, be 2-thienyl groups.
The compounds of formula I as hereinbefore defined 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, hydriodic, nitric, sulphuric, phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic and aspartic acids, alkanesulphonic acids (e.g. methanesulphonic acid) and arylsulphonic acids (e.g. benzenesulphonic acid).
As examples of the preferred compounds according to the invention, particular reference may be made to those compounds of formula I, and acid addition salts thereof, wherein one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups.
12~
Also as examples of preferred compounds according the invention, ~ention may be made of those compounds of formula I, and acid addition salts thereof, wherein one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups and R2 reprensents a hydroglen atom, a straight-chained or branched Cl 6 alkyl group, a methoxycarbonyl group or a phenyl group optionally substituted by one or more halogen atoms or methyl, methoxy or nitro groups.
As examples of especially preferred compounds accor-ding to the invention,mention may be made of those com-^
pounds of formula I, and acid addition salts thereof, wherein one of both of R and R3 represent hydrogen atoms or methyl or ethyl groups, R2 represents a phenyl group and Rl repre-sents a l-methylcyclohexyloxy or l-adamantyloxy group.
More particularly preferred compounds according to the invention include:
l-methylcyclohexyl ~-methyl-2-oxo-4-phenyl-2H-pyrimid~ ,1-b~benzothiazole-8-acetate;
l-adamantyl a-methyl-2-oxo-4-phenyl-2H-pyrimido-L2,1-b] benzothiazole-8-acetate;
and aci~ addition salts of these compounds.
The process for the preparation of the novel pyrimi-do/2,1-b/benzothiazoles of formula I and their pharmaceuti-cally acceptable acid addition salts according the invention, comprises reacting a compound of formula II
R ~ ~ H2 R3 ~ (II) OR
(wherein R, Rl and R3 are as hereinbefore defined) with a compound of formula III
R2_c_c_.co2R4 (III) . : . . ..
~ Z86~9~
(wherein R2 is as hereinbefore defined and R4 represents an alkyl group, preferably a Cl_3 alkyl group) to give a corresponding compound of formula I which is isolated, and, if desired, salified/or which is transesterified by an alcohol of formula IV
H-R' (IV) (~-herein R'l represents a C7 12 straight chained, branched or cyclic alkoxy group) to aive a correspording compound of formula I wherein R1 has the mearing of R'l, which is isolated and,if desire~,salified.
The above process of the invention is preferably carriea out in the following manner.
The reaction of the 2-aminobenzothiazole of formula II with the propiolate of formula III may be effected under reflux and in the presence of an alcohol such as ethanol and a catalyst such as palladium.
~owever, the reaction is preferably effected under heating, e.g. to 100-180C, and in the absence of a solvent.
Alternatively, the process for the preparation of the compounds of formula I, according of the invention, comprises reacting a compound of formula V
R3R "~'~=
0~ 1 -~L2~36Z90 Iwherein R "l represents a hydroxy group or a Cl 6 alkoxy group) with an alcohol of formula VI
H-Rl (VI) (wherein Rl represents a C7 12 straight-chained, branched or cyclic alkoxy group), to give a corresponding compound of formula I which is isolated and, if desired, salified.
The compounds of formula I obtained from either of the processes described above may subsequently be converted into the acid addition salts thereof, particularly the phy-siologically acceptable acid addition salts thereof with inorganic or organic acids, by any conventional method such as for example by reacting the compounds as bases with a solution of the corresponding acid in a suitable solvent.
Conversely, the acid addition salts of the compounds of for-mula I may, if desired subsequently be converted into com-pounds of formula I.
The compound according to the present invention haveinteresting pharmacological properties. In particular, com-pounds which have been tested exhibit remarkable antiallergic properties. These properties are illustrated by experimental test results given hereinafter. It will be appreciatedtherefore that the compounds according to the invention may be useful in medecine. For pharmaceutical use, it will of course be the case that the acid addition salts of the com-pounds of formula I will be physiologically acceptable. Other acid addition salts may, however, `" ~L2 find use, for example in the preparation of compounds of formula I and their physiologically acceptable acid addition salts.
The compounds of formula I and physiologically acceptable acid addition salts thereof may thus find use in the treatment of allergy in the human or ar.imal body.
Preferred in this connection are compounds of formula I wherein one or both o~ R and R3 represent hydrogen atoms or methyl or ethyl groups and physiolog-ically acceptable acid addition salts of such compounds.
Also preferred are compounds of formula I wherein one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups and R2 represents a hydrogen atom, a straisht-chained or branched Cl ~ alkyl g~oup, a methoxycarbonyl group or a phenyl group optionally substituted by one or more halogen atoms or methyl, nitro or methoxy groups and physiologically acceptable acid addition salts of such compounds. Especially preferred are compounds of formula I wherein one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups, R2 represents a phenyl group and Rl represents a l-methylcyclohexyloxy or l-adamant-yloxy group and physiologically acceptable acid addition salts of such compounds.
Particularly suitable for use as medicaments are the following compounds:
l-methylcyclohexyl ~-methyl-2-oxo-4-phenyl-2~-pyrimido[2,1-b]benzothiazole-8-acetate;
l-adamantyl ~-methyl-2-oxo-4-phenyl-2H-pyrimido-~2,1-b]benzothiazole-8-acetate;
and their physiologically acceptable acid addition salts.
Such compounds may have utility for example in the treatment of allergic asthma and asthmatiform bronchitis o~ allergic origin.
, 86~90 The compounds of formula I and their physiologically acceptable acid addition salts may be used to prepare pharmaceutical compositions containing as active ingredient at least one compound of formula I or a physiologically acceptable acid addition salt thereof in admixture with at least one pharmaceutical carrier and/or excipient.
For pharmaceutical administration, the compounds of formula I and their physiologically acceptable acid addition salts may for example be incorporated in compositions for oral, re~:tal and parenteral (including topical) administration, optionally in conjunction with 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 ~0 capsules, granules, 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 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.
Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units for adult human treatment may contain from 0.1 to 1,000 mg, preferably from 1 to 200 mg, of ac~ive inqredient. The daily dosage will vary depending on the product employed but will generally be in the range 1 to 1,000 mg per day for oral 862~) administration for adult human treatment.
Certain compounds of formula II used as starting materials for the preparation of the compounds of formula I are known compounds being described by, for example, S.N. Sawhney et al. in Ind. J.
Chem., 16~, 605 (1978), and in German Offenlegungsschrift 2,015,158; US Patent No. 3,656,958 and European laid-open Patent Application No. 01,017,543. However certaincompounds of formula II are novel.
- The compounds of formula II wherein R and R3 represent hydroqen atoms which are not known ~5 from the literature may be prepared from p-nitrophenyl-acetic acid according to the following reaction scheme:
~t~ 0~ Pd-C
~ H~S04 ~ H2 COO~ COR1 EtOH CORt AcOH ~ N~
Br2 ~ ~/>--NH2 CORl (wherein Rl is as hereinbefore defined).
Compounds oE formula II which are not known Erom the literature may also he prepared from ~-phenyl aldehydes by the following reaction scheme:
1~8~i290 _ R3~ 3~3 R3~/
_~ ~ 10% Pd-~ ~ NH2 KSCN
H ~ R ~ ~VII) R ~ AeOH~r2_ r R ~ \ ~ NH2 (wherein R, Rl and R3 are as hereinbefore defined).
~ here compounds in which R and R3 are Cl 6 alkyl groups are to be prepared, it is preferable S to prepare the intermediate of formula VII in`the above reaction scheme by the alkylation of an intermediate of formula VIII
H ~ No2 (VIII) CORl (wherein R is a Cl_6 alkyl group and Rl is as hereinbefore defined) using for example an alkyl iodide R3I
and a base such as lithium diisopropylamide or lithium N-isopropylcyclohexylamide in a suitable , .
.. . . , ~ .
- lZ~6290 solvent such as tetrahydrofuran. The preparation of the intermediates of formula V~} themaeLyes ls described ~urther below.
The compounds of formula II wherein the moiety R3RC~ represents a group of formula CH3CH may in an alternative process be prepared from 2-phenyl-propionic acid by the following reaction scheme:
R1-H/HCl ~ HN03 ~ 2 c~ C~
OOH CO~l COR1 ~ C~ ;~, ~ r ORl ~R1 twherein Rl is as hereinbefore defined).
The compounds of formula II wherein R3 (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 al. in J. Med. Chem., 26, 222-226 (1983)]:
128~29l0 ~ 1) Na~/DM~O or DMF ~
Cl ~ 2 ~C~2c- ~ 2 2) RCH~C02C2H~)2 (not lsolated) ~; NaOH/H20/C2~50H
/ 2) HCl R R
Rl-- ~N02 C2H COR1 (VIII) / ~ Pd-C
fr--~ CH3COOH R ~ N
H ~ NH XSCN ~ ~ ~ NH2 CORl COR1 (wherein R is a hydrogen atom or a Cl 6 alkyl group, preferably a methyl or ethyl group, and Rl is as hereinbefore defined).
Alternatively, the compounds of formula ~ 2 CH ¦ ll ,~, CoRl ~2~6290 ~wherein Rl is as hereinbefore defin~ed) may be prepared from 2-~p-nitrophenyl)propionic acid by the following reaction scheme~
CH3 ~ ~ 2 1) SOC12 C
H / COOH 2) Ri H ~ / CO-Rl ~ he compounds of formula V ~7herein R, R2 and R3 are as defined hereinbefore and R"l represents a`hydroxy radical or a Cl 6 alkoxy group may be prepared according to the process described in European ~aid-open Patent Application n 0 153 230.
The following non-limiting Examples are intended to illustrate the present invention. In these Examples, temperatures are given in C and percentages are by weight unless otherwise indicated.
Example 1: 1-MethYlcyclohexyl -methyl-2-oxo-4-phenyl-2H-Pyrimido[2,1-b]benzothiazole-8-acetate Step A: l-Methylcyclohexyl 2-(p-nitrophenyl)propionate.
A stirred mixture of 2-~p-nitrophenyl)propionic acid (97.5 9) [see J. Med. Chem., 26, 222-226 (1983)], thionyl chloride (40 ml) and ~ry toluene (500 ml) was heated at 80C for 5 hours. The mixture was then allowed to cool and the solvent removed under reduced pressure. The residual oil was dissolved in dry toluene (400 ml), and l-methylcyclohexanol (100 9) was then added to the solution. The stirred mixture was heated at 80C for 1 hour and then at ambient temperature overnight. The solution was washed with 5% NaHCO3 solution, then water, dried over MgSO4 and finally evaporated to dryness.
The crude mixture was purified on a column ~600 9 silica) using C'~C13 as the eluant, giving l-methyl-cyclohexyl 2-(p-nitrophenYl)propionate as a golden yellow liquid (34.95 g, 24% yield).
}R vmax (thin film): 2940, 1725 (ester), 1520, 1345 and 1150 cm 1 Step B: l-Methylcyclohexyl~2-(p-aminophenyl)propionate.
A stirred solution of l-methylcyclohexyl 2-(p-nitrophenyl)propionate (34.9 g) in absolute ethanol (250 ml) was hydrogenated at atmospheric pressure in the presence of 10% palladium on carbon catalyst. After the uptake of hydrogen gas was complete, the catalyst was ~iltered off through CELITE~ and the filtrate evaporated to dryness.
Trituration of the residue with petroleum ether gave l-met~ylcYclohexyl 2-(p-aminophenYl)propionate lX8629~
_ 14 _ as creamy white crystals (21.02 9, 6796 yield)O
M.p.: 85-87C.
IR vmax (KBr~: 3640 (-NH2), 3370 (-N~I2), 2940, 1710 and 1215 cm 1, Step C: l-Methylcyclohexyl 2-amino-~-methylbenzothiazole-6-acetate.
A stirred mixture of l-methylcyclohexyl 2-(p-aminophenyl)propionate ~20.9 g) and potassium 10 thiocyanate (31.0 g) in glacial ac~tic acid (150 ml) was heated in an oil bath at 50C and a solution of Br2 (25.6 g) in glacial ac~etic acid (15 ml) was added dropwise over 30 mins. The mixture was stirred at 50C for an extra 30 mins, then cooled and poured 15 into a 3:2 water/ethyl acetate mixture (1,000 ml).
The resulting mixture was neutralised to pH 5-6 using solid NaCO3 and filtered through CELITE
and the orgarlic layer was then separated, washed with water, dried over MgSO,t and finally evaporated 20 to dryness. Trituration of the residual oil with petroleum ether gave l-methYlcYclohexyl 2-amino-c~-methYlbenzothiazole-6-acetate as creamy white crystals (18.62 g, 73Y6 yield).
M.p.: 165-167C.
25 IR vmax (KBr): 3410, 2930, 1710 (ester), 1550 and 1215 cm Step D: l-Methylcyclohexyl a-methyl-2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole-8-acetate.
A stirred mixture of l-methylcyclohexyl 2-amino-~-methylbenzothiazole-6-acetate (3.2 91 and ethyl phenylpropiolate (3.5 9) was heated in an oil bath (160C) for 30 mins during which time a further 3.5 g of ethyl phenylpropiolate was added 35 dropwise. The mixture was then cooled to 60C
and ether (30 ml) was added cautiously. Further cooling gave 1-methYlcyclohexyl c~-methyl-2-oxo-* trade mark ~ r~
~X86X9~3 4-phenYl-2~-Pyrimid-ol2~l-b]benzothiazole-8-acetate as pale yellow crystals ~1.82 g, 41% yield).
M.p.: 168-170C.
IR ~max (~Br): 2930, 1720 (e5ter), 1650, 1510 and S 1145 cm Analysis:
Calculated %C 69 . 93, ~H 5.87, %N 6.27, %S 7.18.
Found %C 69.87, %~ 5.90, ~N 6.23, %s 7.23.
Example 2: l-Adamantyl ~-methYl-2-oxo-4-phenyl-2~-pyrimido[2 r 1-b]benzothiazole-8-acetate Step A: l-Adamantyl 2-(p-nitrophenyl)propionate.
~ sing a method similar to that used in the preparation of l-methylcyclohexyl 2-(p-nitrophenyl)propionate starting from 2-(p-nitrophenyl)propionic acid (14.6 9)~
but using l-adamantanol instead of l-methylcyclohexanol, the desired product was obtained as a light yellow viscous liquid t22.74 9, 92% yield).
IR ~max (thin film): 2920, 1725 (ester), 1520, 1345 and 1055 cm 1.
Step B: l-Adamantyl~ 2-(p-aminophenyl)propionate.
Using a method similar to that used in the preparation of l-methylcyclohexyl 2-(p-aminophenyl)-propionate, but starting from l-adamantyl 2-(p-nitrophenyl)propionate (21.4 9), the title comPound was obtained as a light yellow viscous liquid (19.42 9, 100% yield).
IR ~max (thin film): 3450 (-NH2), 3370 (-NH2), 2910, 172Q (ester) and 1055 cm 1 Step C: l-Adamantyl 2-amino-~-methylbenzothiazole-6-acetate.
Using a method similar to that used in the preparation of l-methylcyclohexyl 2-amino-~-methyl-benzothiazole-6-acetate, but starting from l-adamant-yl 2-(p-aminophenyl)propionate (19.1 g), the ~28~2~3 _ 16 _ title comPound was obtained as a creamy white solid (lB.97 g, 83% yield~.
M.p.: 151-153C.
IR ~max (RBr): 3400, 2910, 1710 (ester), 1540 and 1210 cm~l.
Step D: l-~damantyl ~-methyl-2-oxo-4-phenyl-2R-pyrimido[2,1-b~benzothiazole--8-acetate.
Using a method similar to that used in the preparation of l-methylcyclohexyl ~-methyl-2-oxo-4-phenyl-2~-pyrimidot2,1-b]benzothiazole-8-acetate, but starting from l-adamantyl 2-amino-~-methyl-benzothiazole-6-acetate (8.9 9) and heating at 160C for 1 hour, the title compound was obtained lS as a light yellow solid after recrystallisation from ethyl acetate/petroleum ether (4.73 9, 39%
yiela) .
M.p.: 188-190C.
IR ~max (RBr): 2910, 1720 (ester), 1640, 1510 and 1390 cm 1 Analysis:
Calculated %C 71.88, %H 5.82, %N 5.78, ~S 6.62.
Found %C 71.71, %H 5.87, %N 5.75, %S 6.57.
Example 3 Tablets were prepared according to the formulation:
- compound of Example 1...................... ..15 mg - excipient g.s. for one tablet up to........ .100 mg.
(Details of the excipient : lactose, starch, talc, maynesium stearate).
Example 4 A dosed aerosol was prepared delivering per dose:
- compound of Example 2...................... .2 mg - emulsifier................................ 0.15 mg 35 - propellant................................. 50 mg.
ExamPle 5 Tablets were prepared according to the formulation:
- compound of Example 2..................... ..15 mg - excipient q.s. for one tablet up to ...... 10~ mg.
(Details of the excipient : lactose, starch, talc, magnesium stearate) PHARMACOLOGICAL ACTIVITY
Test : Antiqen induced elevation of lung perfusion 10 Pressure Animals Male Dunkin ~artley guinea pigs (Porcellus, 450-700 g) are used (four per drug concentration) housed in cages. Animals are sensitised by two ~ee~ly exposures to aerosol ovalbumen (1% W/V).
Druqs Animals are anaesthetised with 2.5 mg/kg diazepam i.p. and 1 ml/kg ~ypnorm 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.
Lungs are perfused with aerated krebs fluid (95 2 : 5% CO2) at 37C. Ovalbumen (5~9 in 0.lml) is injected through an injection port proximal to each lung. Elevation of perfusion pressure by the antigen is recorded. Sixty minutes later, 15 pg ovalbumen is administered. Research compounds are added to the krebs fluid reservoir, thirty minutes prior to the second antigen dose. For each weekly batch of animals used, control measurements 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 tfrom four different animals) ~.2~6290 are used per concentration. Percentage inhibition of antigen induced bronchoconstriction is calculated 50 1~) Results are given in Table I below.
Table I
. _ ._ _ Product of Example IC50 ~M
_ __ _ , . .. _
Claims (24)
1. A process for preparing a compound of formula I
(I) wherein R and R3, which may be the same or different, each represents a hydrogen atom or a straight-chained or branched C1-6 alkyl group or together with the intervening carbon atom represent a C3-6 cycloalkyl group; R1 represents a C7-12 straight-chained, branched or cyclic alkoxy group; and R2 represents a hydrogen atom, a straight-chained or branched C1-6 alkyl group, a C2-7 alkoxycarbonyl group, a C3-6 cycloal-kyl group, a benzyl group, a C6-12 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 containing one or more sulphur atoms in the aryl ring-and its pharmaceutically acceptable acid addition salts, which comprises either reacting a compound of formula II
(II) (wherein R, R1 and R3 are as hereinbefore defined) with a compound of formula III
R2-C?C-CO2R4 (wherein R2 is as hereinbefore defined and R4 represents an alkyl group) to give a corresponding compound of formula I
which is isolated, and, if desired, salified, or which is transesterified by an alcohol of formula IV
H-R'1 (IV) (wherein R'1 represents a C7-12 straight chained, branched or cyclic alkoxy group) to give a corresponding compound of formula I wherein R1 has the meaning of R'1, which is isolated and, if desired, sulfide, or reacting a compound of formula V
(V) (wherein R"1 represents a hydroxy group or a C1-6 alkoxy group) with an alcohol of formula VI
H-R1 (VI) (wherein R1 represents a C7-12 straight-chained, branched or cyclic alkoxy group), to give a corresponding compound of formula I which is isolated and, if desired, salified.
(I) wherein R and R3, which may be the same or different, each represents a hydrogen atom or a straight-chained or branched C1-6 alkyl group or together with the intervening carbon atom represent a C3-6 cycloalkyl group; R1 represents a C7-12 straight-chained, branched or cyclic alkoxy group; and R2 represents a hydrogen atom, a straight-chained or branched C1-6 alkyl group, a C2-7 alkoxycarbonyl group, a C3-6 cycloal-kyl group, a benzyl group, a C6-12 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 containing one or more sulphur atoms in the aryl ring-and its pharmaceutically acceptable acid addition salts, which comprises either reacting a compound of formula II
(II) (wherein R, R1 and R3 are as hereinbefore defined) with a compound of formula III
R2-C?C-CO2R4 (wherein R2 is as hereinbefore defined and R4 represents an alkyl group) to give a corresponding compound of formula I
which is isolated, and, if desired, salified, or which is transesterified by an alcohol of formula IV
H-R'1 (IV) (wherein R'1 represents a C7-12 straight chained, branched or cyclic alkoxy group) to give a corresponding compound of formula I wherein R1 has the meaning of R'1, which is isolated and, if desired, sulfide, or reacting a compound of formula V
(V) (wherein R"1 represents a hydroxy group or a C1-6 alkoxy group) with an alcohol of formula VI
H-R1 (VI) (wherein R1 represents a C7-12 straight-chained, branched or cyclic alkoxy group), to give a corresponding compound of formula I which is isolated and, if desired, salified.
2. A process for the preparation of a compound of formula I as claimed in claim 1, which comprises reacting a compound of formula II
(II) (wherein R, R1 and R3 are as defined in claim 1) with a compound of formula III
R2-C?C-CO2R4 (III) (wherein R2 is as defined in claim 1 and R4 represents an alkyl group) to give a corresponding compound of formula I
which is isolated, and, if desired, salified, or which is transesterified by an alcohol of formula H-R'1 (IV) (wherein R'1 represents a C7-12 straight chained, branched or cyclic alkoxy group) to give a corresponding compound of formula I wherein R1 has the meaning of R'1 which is isolated and, if desired, salified.
(II) (wherein R, R1 and R3 are as defined in claim 1) with a compound of formula III
R2-C?C-CO2R4 (III) (wherein R2 is as defined in claim 1 and R4 represents an alkyl group) to give a corresponding compound of formula I
which is isolated, and, if desired, salified, or which is transesterified by an alcohol of formula H-R'1 (IV) (wherein R'1 represents a C7-12 straight chained, branched or cyclic alkoxy group) to give a corresponding compound of formula I wherein R1 has the meaning of R'1 which is isolated and, if desired, salified.
3. A process according to claim 2 wherein the reaction is effected under reflux in the presence of an alcohol and a catalyst.
4. A process according to claim 3 wherein the alcohol used is ethanol and the catalyst used is palladium.
5. A process according to claim 2 wherein the reaction is effected by heating to 100-180°C in the absence of a solvent.
6. A process according to claim 2 wherein in the starting compound of formula III, R4 represents a C1-3 alkyl group.
7. A process according to claim 2, wherein in the starting compound, one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups.
8. A process according to claim 2 wherein in the starting compound, one or both of R and R3 represent hydro-gen atoms or methyl or ethyl groups and R2 represents a hy-drogen atom, a straight-chained or branched C1-6 alkyl group, a methoxycarbonyl group or a phenyl group optionally substi-tuted by one or more halogen atoms or methyl, methoxy or nitro groups.
9. A process according to claim 2, wherein in the starting compound, one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups, R2 represents a phenyl group and R1 represents a 1-methylcyclohexyloxy or 1-adamantyloxy group.
10. A process for the preparation of a compound of formula I as claimed in claim 1, which comprises reacting a compound of formula V
(V) (wherein R, R2 and R3 are as defined in claim 1 and R"1 represents a hydroxy group or a C1 6 alkoxy group) with an alcohol of formula VI
H-R1 (VI) (wherein R1 represents a C7-12 straight-chained, branched or cyclic alkoxy group), to give a corresponding compound of formula I which is isolated and, if desired, salified.
(V) (wherein R, R2 and R3 are as defined in claim 1 and R"1 represents a hydroxy group or a C1 6 alkoxy group) with an alcohol of formula VI
H-R1 (VI) (wherein R1 represents a C7-12 straight-chained, branched or cyclic alkoxy group), to give a corresponding compound of formula I which is isolated and, if desired, salified.
11. A process according to claim 10 wherein in the starting compound, one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups.
12. A process according to claim 10 wherein in the starting compound, one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups and R2 represents a hydrogen atom, a straight-chained or branched C1-6 alkyl group, a methoxycarbonyl group or a phenyl group optionally substitu-ted by one or more halogen atoms or methyl, methoxy or nitro groups.
13. A process according to claim 10, wherein in the starting compound, one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups, R2 represents a phenyl group and R1 represents a 1-methylcyclohexyloxy or 1-adamantyloxy group.
14. A process for preparing 1-methylcyclohexyl-.alpha.
methyl-2-oxy-4-phenyl-2H-pyrimido/2, 1-b/benzothiazole-8-acetate and its pharmaceutically acceptable acid addition salts, which comprises reacting 1-methylcyclohexyl 2-amino-.alpha.-methylbenzothiazole-8-acetate with ethyl phenylpropiolate and, if desired, salifying the so obtained product.
methyl-2-oxy-4-phenyl-2H-pyrimido/2, 1-b/benzothiazole-8-acetate and its pharmaceutically acceptable acid addition salts, which comprises reacting 1-methylcyclohexyl 2-amino-.alpha.-methylbenzothiazole-8-acetate with ethyl phenylpropiolate and, if desired, salifying the so obtained product.
15. A process for preparing 1-adamantyl-.alpha.-methyl-2-oxy-4-phenyl-2H-pyrimido/2,1-b/benzothiazole-8-acetate and its pharmaceutically acceptable acid addition salts, which comprises reacting 1-adamantyl 2-amino-.alpha.-methylbenzothiazo-le-8,-acetate with ethyl phenylpropiolate and, if desired, salifying the so obtained product.
16. A compound of formula I:
(I) wherein R and R3, which may be the same or different, each represents a hydrogen atom or a straight-chained or branched C-6 alkyl group or together with the intervening carbon atom represent a C3-6 cycloalkyl group; R1 represents a C7-12 straight-chained, branched or cyclic alkoxy group; and R2 represents a hydrogen atom, a straight-chained or branched C1-6 alkyl group, a C2-7 alkoxycarbonyl group, a C3-6 cycloalkyl group, a benzyl group, a C6 12 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 containing one or more sulphur atoms in the aryl ring, and its pharmaceutically acceptable acid addition salts.
(I) wherein R and R3, which may be the same or different, each represents a hydrogen atom or a straight-chained or branched C-6 alkyl group or together with the intervening carbon atom represent a C3-6 cycloalkyl group; R1 represents a C7-12 straight-chained, branched or cyclic alkoxy group; and R2 represents a hydrogen atom, a straight-chained or branched C1-6 alkyl group, a C2-7 alkoxycarbonyl group, a C3-6 cycloalkyl group, a benzyl group, a C6 12 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 containing one or more sulphur atoms in the aryl ring, and its pharmaceutically acceptable acid addition salts.
17. A compound of formula I as defined in claim 16, wherein one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups.
18. A compound of formula I as defined in claim 16, wherein one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups and R2 represents a hydrogen atom, a straight-chained or branched C1-6 alkyl group, a methoxy-carbonyl group or a phenyl group optionally substituted by one or more halogen atoms or methyl, methoxy or nitro groups.
19. A compound of formula I as defined in claim 16, wherein one or both of R and R3 represent hydrogen atoms or methyl or ethyl groups, R2 represents a phenyl group and R1 represents a 1-methylcyclohexyloxy or 1-adamantyloxy group.
20. 1-Methylcyclohexyl-.alpha.-methyl-2-oxo-4-phenyl-2H-pyrimido/2,1-b/benzothiazole-8-acetate.
21. 1-Adamantyl-.alpha.-methyl-2-oxo-4-phenyl-2H-pyri-mido/2,1-b/benzothiazole-8- acetate.
22. A pharmaceutical composition comprising an effective amount of a compound of formula (I) as defined in claim 16 in admixture with a pharmaceutically acceptable carrier.
23. A pharmaceutical composition comprising an effective amount of a compound of formula (I) as defined in claim 17, 18 or 19 in admixture with a pharmaceutically acceptable carrier.
24. A pharmaceutical composition comprising an effective amount of a compound as claimed in claim 20 or 21 in admixture with a pharmaceutically acceptable carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB858519261A GB8519261D0 (en) | 1985-07-31 | 1985-07-31 | Chemical compounds |
| GB8519261 | 1985-07-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1286290C true CA1286290C (en) | 1991-07-16 |
Family
ID=10583097
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000514995A Expired - Fee Related CA1286290C (en) | 1985-07-31 | 1986-07-30 | Anti-allergic pyrimido[2,1-l-b]benzothiazoles |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0211759B1 (en) |
| JP (1) | JPS6229592A (en) |
| KR (1) | KR870001221A (en) |
| AT (1) | ATE62689T1 (en) |
| AU (1) | AU586010B2 (en) |
| CA (1) | CA1286290C (en) |
| DE (1) | DE3678764D1 (en) |
| DK (1) | DK361286A (en) |
| ES (1) | ES2002111A6 (en) |
| FI (1) | FI863118A (en) |
| GB (2) | GB8519261D0 (en) |
| GR (1) | GR862015B (en) |
| HU (1) | HU194895B (en) |
| NZ (1) | NZ217026A (en) |
| PT (1) | PT83099B (en) |
| SU (1) | SU1544191A3 (en) |
| ZA (1) | ZA865170B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8403739D0 (en) * | 1984-02-13 | 1984-03-14 | Roussel Lab Ltd | Chemical compounds |
| GB8522186D0 (en) * | 1985-09-06 | 1985-10-09 | Erba Farmitalia | Cycloalkyl-substituted 4-aminophenyl derivatives |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3919201A (en) * | 1970-09-30 | 1975-11-11 | Lilly Industries Ltd | 2-({62 -Aminoacryloyl)iminobenzothiazolines |
| DE2810863A1 (en) * | 1978-03-13 | 1979-09-27 | Boehringer Mannheim Gmbh | 1-OXO-1H-PYRIMIDO ANGLE CLAMP ON 6.1-B ANGLE CLAMP ON BENZTHIAZOLE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| GB8403739D0 (en) * | 1984-02-13 | 1984-03-14 | Roussel Lab Ltd | Chemical compounds |
-
1985
- 1985-07-31 GB GB858519261A patent/GB8519261D0/en active Pending
-
1986
- 1986-07-10 ZA ZA865170A patent/ZA865170B/en unknown
- 1986-07-23 JP JP61171948A patent/JPS6229592A/en active Pending
- 1986-07-30 ES ES8600714A patent/ES2002111A6/en not_active Expired
- 1986-07-30 GR GR862015A patent/GR862015B/en unknown
- 1986-07-30 SU SU864027859A patent/SU1544191A3/en active
- 1986-07-30 AU AU60687/86A patent/AU586010B2/en not_active Ceased
- 1986-07-30 FI FI863118A patent/FI863118A/en not_active Application Discontinuation
- 1986-07-30 DK DK361286A patent/DK361286A/en not_active Application Discontinuation
- 1986-07-30 CA CA000514995A patent/CA1286290C/en not_active Expired - Fee Related
- 1986-07-30 PT PT83099A patent/PT83099B/en not_active IP Right Cessation
- 1986-07-30 NZ NZ217026A patent/NZ217026A/en unknown
- 1986-07-30 GB GB8618641A patent/GB2178429B/en not_active Expired
- 1986-07-31 HU HU863299A patent/HU194895B/en not_active IP Right Cessation
- 1986-07-31 EP EP86401707A patent/EP0211759B1/en not_active Expired - Lifetime
- 1986-07-31 DE DE8686401707T patent/DE3678764D1/en not_active Expired - Fee Related
- 1986-07-31 AT AT86401707T patent/ATE62689T1/en active
- 1986-07-31 KR KR1019860006314A patent/KR870001221A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU586010B2 (en) | 1989-06-29 |
| ES2002111A6 (en) | 1988-07-16 |
| HU194895B (en) | 1988-03-28 |
| ZA865170B (en) | 1987-09-30 |
| PT83099A (en) | 1986-08-01 |
| KR870001221A (en) | 1987-03-12 |
| JPS6229592A (en) | 1987-02-07 |
| HUT42776A (en) | 1987-08-28 |
| EP0211759A2 (en) | 1987-02-25 |
| DK361286D0 (en) | 1986-07-30 |
| DK361286A (en) | 1987-02-01 |
| FI863118A (en) | 1987-02-01 |
| GB8618641D0 (en) | 1986-09-10 |
| FI863118A0 (en) | 1986-07-30 |
| PT83099B (en) | 1988-11-30 |
| GB8519261D0 (en) | 1985-09-04 |
| ATE62689T1 (en) | 1991-05-15 |
| NZ217026A (en) | 1989-02-24 |
| EP0211759A3 (en) | 1988-03-30 |
| AU6068786A (en) | 1987-02-05 |
| DE3678764D1 (en) | 1991-05-23 |
| GB2178429B (en) | 1989-09-13 |
| GB2178429A (en) | 1987-02-11 |
| EP0211759B1 (en) | 1991-04-17 |
| GR862015B (en) | 1986-12-23 |
| SU1544191A3 (en) | 1990-02-15 |
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Legal Events
| Date | Code | Title | Description |
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| MKLA | Lapsed |