FI79323B - FREQUENCY REFRIGERATION FOR THERAPEUTIC THERAPY OF PYRIMIDO / 2,1-B / BENZODIAZOLER. - Google Patents

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

1 79323

Process for the preparation of new therapeutically useful pyrimido-2,1-b7benzothiazoles

The invention relates to a process for the preparation of novel pyrimido [1,2-b] -5-benzothiazoles and their salts. It has been found that these new pyrimido, A2, 1H-benzothiazoles have interesting pharmacological properties, in particular antiallergic effects.

The invention thus relates to a process for the preparation of new therapeutically useful pyrimido [2 ", 1-57benzothiazoles and their salts of the formula 10 (I), * 2" \ rrO- · vU /

R, j X S

CORR20 wherein R and R3, which may be the same or different, each represent a hydrogen atom or a straight-chain or branched C3-8 alkyl group; R 1 denotes a hydroxy group, a straight-chain or branched C 3-8 alkoxy group or a group of the formula ... -n D (A), in which R c and R 1 may be the same or different from each other, each represents a hydrogen atom or a C 1-6 alkyl group or together with an intervening nitrogen atom form a piperidino or morpholino group; and R 3 represents a hydrogen atom or a straight-chain or branched C 3-8 alkyl, C 2-6 alkoxycarbonyl or C 3-8 cycloalkyl group or a phenyl, alkylphenyl, alkoxyphenyl, halophenyl, nitrophenyl or benzyl group.

U.S. Patent Nos. 2,79,323, 3,813,360, 3,919,201 and 3,538,086 and Journal of Medicinal Chemistry 15 (1972): 12, pp. 1203-6 describe similar types of pyrimido- (2,1) / benzothiazole derivatives in which The backbone is analogous to the compounds of the present invention, but the substituents are very different, and the pharmacological properties of the compounds described in these publications are different from those of the compounds of the present invention.

FI patent publication 60871 describes antiallergically active pyrimido [1, b] benzothiazole compounds, however, the structure of these compounds differs from the compounds prepared according to the invention, e.g. with regard to groups in the 3- and 8-15-positions. In addition, the ketone group is in the 4-position and not the 2-position in the compounds according to FI patent publication 60871.

With respect to the above formula (I), said straight-chain or branched C 1-6 alkyl groups may be, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl groups. . Straight-chain or branched C 1-6 alkoxy groups can be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy or hexyloxy.

The C 1-8 cycloalkyl groups may be, for example, cyclohexyl groups. The C 2-7 alkoxycarbonyl groups may be, for example, methoxycarbonyl, ethoxycarbonyl or iso-propoxycarbonyl groups. Said halogen atoms may be, for example, chlorine, fluorine or bromine atoms.

The compounds of formula (I) having a hydroxy group are acidic in nature and may form salts with metals or nitrogen bases. The metal salts may be, for example, alkali metal salts such as sodium, potassium and lithium salts, alkaline earth metal salts such as calcium salts, or salts formed by metals such as aluminum and magnesium. Salts of nitrogen bases include, for example, ammonium salts and salts of amines such as tromethamine and triethanolamine, as well as lysine and arginine.

Those compounds of formula I having an alkoxy group or a group of formula A are basic in nature and may form acid addition salts.

Acid addition salts may be formed with inorganic or organic acids; they may be, for example, salts formed with hydrogen chloride, hydrogen bromide, iodine-10 hydrogen, nitrogen, sulfur, phosphorus, propionic, acetic, non-monetary, benzoic, maleic, fumaric, amber with tartaric, citric, oxalic, glyoxylic and aspartic acid, alkali sulfonic acids (e.g. methanesulfonic acid) and arylsulfonic acids (e.g. benzenesulfonic acid) 15. However, such salts may be sensitive to hydrolysis in water to form the free base.

Examples of preferred compounds obtainable by the process of the invention include those compounds of formula (I) in which either or both of R 1 and R 2 are hydrogen atoms or methyl or ethyl groups, and their salts.

Preferred compounds obtainable by the process of the invention may also be mentioned as those of formula (I). wherein one or both of R and are hydrogen atoms or methyl or ethyl groups and R 2 is a hydrogen atom or a straight-chain or branched C 1-8 alkyl, methoxycarbonyl or phenyl group, the latter being optionally substituted by one or more halogen atoms or -, with 30 methoxy or nitro groups.

Particularly preferred compounds obtainable by the process of the invention are, for example: ethyl (2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate); 35 ethyl [7: oxo-4- (p-methoxyphenyl) -2H-pyrimido [2,1-b] benzothiazole-8-acetate; -> 79323 ethyl [2-oxo-4- (o-chlorophenyl) -2H-pyrimido] -2,1-b (benzothiazole-8-acetate); ethyl (methyl 2-oxo-4-phenyl-2H-pyrimido [1,2-b] benzothiazole-8-acetate); 5 ethyl N-methyl-2-oxo-4- (p-chlorophenyl) -2H-pyrimido-1,2,1-benzothiazole-8-acetate; ethyl (-N-ethyl-2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate); and their salts.

In the process of the invention for the preparation of novel pyrimido [1,2-b] benzothiazoles of the formula (I), it is characterized in that the compound of the formula (II)

15 - N

y \\ R! jj \\ - NH2 <ij> V - COR '1 20 where R and R1 are as defined above and R | represents a C 1-6 alkoxy group, is reacted with a compound of formula (III) R 2 -C = C-CO 2 R 4 (III) wherein R 2 is as defined above and R 1 represents an alkyl group to give a compound of formula (Ia), R 2 ^ 30

- N> == O

R! \ _ "= Ν '\ /' ^ V (^ ^ 35 toR'l where R, R3, R ^ 'and R2 are as defined above, after which, if desired, the compound of formula {IA> is saponified to give the formula (Ig ),

10 COOH

wherein R 1 and R 2 are as defined above, and then, if desired, reacting a compound of formula (Ig) with a compound of formula 15

HN

^ R6 where R1. and R 9 are as defined above to give a compound of formula I wherein R 1 is

20 R

The compounds thus obtained are isolated and, if desired, their salts are formed by conventional methods.

The above process according to the invention is carried out as follows.

The reaction of a 2-aminobenzothiazole of formula (II) with a propiolate of formula (III) can be carried out, with R 2 preferably being hydrogen at reflux and in the presence of an alcohol such as ethanol and a catalyst such as palladium. In the case of a propiolate of the formula (III) in which R 2 is other than hydrogen, the reaction is preferably carried out without a solvent, for example at a temperature of 100 to 180 ° C.

6 79323

The saponification of a compound of formula (I) having an alkoxy group is preferably carried out using a weak base such as potassium carbonate.

Reaction of a compound of formula ID with a compound

D

5 sa of the formula HNR ^ Rg is carried out in the presence of 1,1-diimidazole.

Salts of compounds of formula (I) wherein R 1 is a hydroxy group with metal ions or nitrogen bases may be prepared by reacting said compounds of formula (I) 10 with an appropriate base such as an alkali metal or alkaline earth metal base or nitrogen base.

Acid salts of compounds of formula (I) wherein R 1 is an alkoxy group or a group of formula -NR 2 R 4 may be prepared by reacting said compounds of formula (I) with the appropriate acid.

The compounds of the invention have interesting pharmacological properties. In particular, the compounds tested have significant antiallergic properties. 20 The test results presented below illustrate these features. The compounds of the invention are thus useful in medicine. For pharmaceutical use, the salts of the compounds of formula I must be physiologically acceptable. However, other salts may have use in the preparation of compounds of the formula I and their physiologically tolerable salts.

Pharmacological activity

Test: Antigen-induced increase in pulmonary perfusion pressure 30 Animals Male Dunkin Hartley guinea pigs (Procellus, 450-700 g; per four drug concentrations) are used in cages. Animals are sensitized by two weekly exposures to aerosol albumin (1% w / v).

35 Medicines

Animals are anesthetized by administration of 2.5 mg / kg di-7 79323 azepam i.p. and 1 ml / kg Hypnormia i.m.

Method

After anesthesia, the animals are bled without cutting both carotid arteries. The thorax is opened, and the 5 lungs are removed, split in half from the Carina, and both main block bronchi are cannulated and connected to the perfusion system. The lungs are perfused with aerated Krebs solution (95% O 2, 5% CO 2) at 37 ° C. Oval-bumin (5 pg in 0.1 ml) is injected through a cannula into the base of each lung. An increase in perfusion pressure due to antigen is recorded. 60 minutes later, 15 pg of ovalbumin is administered. Test compounds are added to a container containing Krebs solution 30 minutes before the second antigen dose. For each weekly group of animals-15, comparative measurements are performed without drug treatment (n = 10).

The second antigen response is expressed as a percentage of the first. At least four lungs (from four different animals) per concentration are used for drug treatment. The percentage inhibition of bronchoconstriction by the anti-20 gene is calculated (IC, -q pM).

The results are shown in Table 2 below.

Table 2

Example according to which IC 50 is μM

the product has been manufactured_ 2> 100 3 1 4 10 5 <10 6 1-10 30 7> 10 9 1 10 10-100 \\ 11 10 12 0.1-1 13 <1 14 <1 35 15 10-100 16 100 17 1-10 8 79323

Table 2 (continued)

Example where I (“50 products are manufactured_ 18 10 20 0.1 5 22 0.1-1 23 <1 24> 10 25 10-100 27 10-100 28 10-100 29 0.1 in 30 1- 10 31 <10 32 1 33 10-100 34 1-10 35 0.1-1 36 1-10 37 1 15 38 1 39 0.1 40 10-100 41 10-100 42 10-100 43 0.1 44 10-100 9n 45 10-100 46> 100 47 10 48 10-100 The compounds of formula (I) and their physiologically acceptable salts thus have use in the treatment of allergies in humans or animals.

Preferred compounds of the formula I in this connection are those in which one or both of the groups R and R 1 are hydrogen atoms or methyl or ethyl groups, and their pharmacologically acceptable salts. Particularly preferred compounds are those compounds of formula I in which one or both of R 1 and R 2 are hydrogen atoms or methyl or ethyl groups and R 2 is a hydrogen atom, a C 1-6 alkyl, methoxycarbonyl or phenyl group which last said being optionally substituted by one or more halogen atoms or methyl, nitro or methoxy groups, and their physiologically acceptable salts.

9 79323

Particularly suitable for use as medicaments are the following compounds: ethyl (2-oxo-4-phenyl-2H-pyrimido [1,1-b] benzothiazole-8-acetate); 5 Ethyl N-oxo-4- (p-methoxyphenyl) -2H-pyrimido [2,1-b] benzothiazole-8-acetate Ethyl ε-2-oxo-4- (o-chlorophenyl) -2H-pyrimido [2,1-b] benzothiazole-8-acetate]; ethyl (* - methyl-2-oxo-4-phenyl-2H -pyrimido [1,2-b] benzo-10-sothiazole-8-acetate), ethyl N-methyl-2-oxo-4- (p-chlorophenyl) -2H-pyrimido-E, 1,1-benzothiazole-8- ethyl acetate (N-ethyl-2-oxo-4-phenyl-2H-pyrimido-2H-2-benzothiazole-8-acetate) and their physiologically acceptable salts.

Such compounds are useful, for example, in the treatment of allergic asthma and allergic asthma-type bronchitis.

The compounds of the formula I and their physiologically tolerable salts can be used for the preparation of pharmaceutical compositions containing. . as active ingredient at least one compound of the formula I or a salt of such a compound in admixture with at least one pharmaceutical carrier and / or excipient.

25 on therapy to administration of a compound of formula I, appropriate connecting roads and their physiologically acceptable salts can be included in the compositions which are suitable for administration via oral, rectal and parenteral administration (topical administration including a), optionally in combination with other active ingredients, 30. The pharmaceutical compositions may be, for example, solid or liquid, presented in conventional human and veterinary dosage forms, for example tablets (either uncoated or coated tablets), gelatin capsules, granules, suppositories, syrups, Aero-35 sols, ointments, salves and ointments. way.

The active ingredient (s) may be combined with excipients conventionally used in pharmaceutical compositions, for example talc, acacia, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, animal or vegetable fats, paraffins, paraffins, various dispersing or emulsifying agents and / or preservatives.

The compositions may conveniently be presented in unit dosage form, each unit containing a predetermined quantity of active ingredient. Dosage units suitable for the treatment of an adult human may contain 0.1 to 100 mg, preferably 1 to 200 mg, of active ingredient. The daily dose varies depending on the product used, but is usually 1-100 mg per day in the case of oral administration to an adult.

Some of the compounds of formula II used as starting materials in the preparation of the compounds of formula I are known compounds described, for example, in the following publications: S.N. Sawhney et al., Ind. J. Chem.

16B (1978) 605; DE-A-2 015 158, U.S. Patent-20-A-656 958 and EP-A-17543A. Some compounds corresponding to formula II

R 1 -NH (II) • R 3 is Y / COR 2 (wherein R 1 and R 3 are as defined above, provided that when R 2 is a hydroxyl group, the group R 1, R 2 is a group other than CH 2 CHCl 3 or TCH 2 and However, when R 1 is an ethoxyl group, the group R 1 (R 2 is other than methylene) and which are useful as intermediates in the preparation of compounds of formula I are novel.

Compounds of formula II in which R and R 2 are hydrogen atoms and which are not known from the literature can be prepared from p-nitrophenylacetic acid according to the following reaction scheme: 11 79323 NO, i - / N ° 2 „ΝΗ *

RrH 10% Pd-C j 5 H2SO4 H2> COOH Cor EtOH and LU RT COR1 ’

AC0H M

KS CN 7- ^ 10 - ^ y-nh2 3r2 f (where R ^ 1 is a C 1-6 alkoxyl group) COR, '15

Compounds of formula II which are not known from the literature can also be prepared from -phenylaldehydes according to the following reaction scheme:

2 ° 7] NH 2 O 2 H 3 HNO

R L '! > R j: · γ, y ^, γ ^

3 CHO 3 CN 3 CN

25 / NO2 NHP

: R1 'H sy' 109 «Pd-C ά KSCN

- - ^ _ «*, Ac0H / Bro

h2so4 r h2 'r I I

iV) r- \ L

3 COR. ' 3 COR 1 30 K f jT V-NH 2 R 3 COR ^ 1 (where R 1 'is a C 1-6 alkoxyl group) i2 79323

When compounds in which R and R 3 are C 1-6 alkyl groups are to be prepared, it is preferable to prepare the intermediate of formula V shown in the above reaction scheme by alkylating an intermediate corresponding to formula VI.

5 R

H - Γ ^ ΝΟ, (VI) „(where R is a C 1-6 alkyl group and R 1 'COR 1) is a C 1-6 alkoxyl group) for example an alkyl iodide R 1 and a base such as lithium diisopropylamide or lithium N-isopropylcyclohexylamide, using in a suitable solvent such as tetrahydrofuran. The preparation of the intermediates of formula VI itself is described in more detail below.

Compounds of formula II in which the group R 2 RC corresponds to the formula CH 2 CH 2. , can be prepared by an alternative method from o6 ′ phenylpropionic acid according to the following reaction scheme: 20 ivh / hc1 HNO3 2 ΓΗ ^ H3 ^.

* L m R 1 CO R -1: C00H COR1 ': 25 NH2

Ho / Pd Y KSCN / Br2 »I JL> - COR ·, '(where R 1' is a C 1-6 alkoxyl group) 13 79323

Compounds of formula II in which (or R) is a hydrogen atom can also be prepared from 1-chloro-2-nitrobenzene according to the following reaction scheme / the first steps of which are based on the reaction scheme discussed by K. Hino et al. in J. Med.

Chem. 26 (1983) 222-226J:

R

j-- 1) NaH / DMSO or DMF ^ Cl -rV10; 10 2) RCH (CO2C2H5) 2 _1 / CO2C2H5 (not isolated)

.X'l) NaOH / H 2 O / C 2 H 5 OH

15 2) HCl S—- -40-¾ CO-H COR. '20 2 1 (VI)

- yS VO \ Pd-C

/ H2 C, H OH 25 30 C0R! 'H COR 1' (wherein R is a hydrogen atom or a C 1-6 alkyl group, preferably a methyl or ethyl group, and R 1 'is a C 1-6 alkoxyl group) The following examples illustrate the invention but do not limit it. In these examples, temperatures are expressed in degrees Celsius and percentages are by weight unless otherwise indicated.

i4 79323

Example 1; Ethyl (2-oxo-2H-pyrimido [1,1-b] [7-benzothiazole-8-acetate

A mixture of ethyl (2-aminobenzothiazole-6-acetate) (5 g), methyl propiolate (1.95 g) and ethanol-30 (30 ml) was stirred and refluxed for 2 h.

The mixture was allowed to cool and the crude product was collected and then recrystallized from n-butanol to give ethyl (2-oxo-2H-pyrimido / 2,1-b) benzothiazole-8-acetate) as yellow needle-like crystals (2.88 g, yield 10 48%).

The starting ethyl (2-aminobenzothiazole-6-acetate) can be prepared according to the method of S. N. Sawhney et al.

/ Ind. J. Chem. 16B (1978) 605J.

Example 2; Ethyl (2-oxo-2H-pyrimido / 2,1-b7-15 benzothiazole-8-o6-methyl acetate

Using a procedure similar to Example 1 but starting from a similar compound of formula II wherein R is methyl / ethyl (2-amino-O-methylbenzothiazole-e-acetate) and methyl propiolate-20 was prepared by refluxing ethyl (2-oxo-ethyl) for 17 h. 2H-pyrimido [2,1-b] benzothiazol-8-ylmethyl acetate) (yield 42%).

The starting ethyl (2-amino-n-methylbenzothiazole-6-acetate) was prepared as follows:

Step A: 2-Amino-o-methylbenzothiazole-6-acetonitrile

To a mixture of 2- (p-aminophenyl) propionitrile (25 g; see, for example, GB 30,198,212), potassium thiocyanate (66.8 g) and 95% acetic acid (300 ml) and stirred, bromine (27.4 g) in 95% acetic acid (87.5 ml) was added dropwise at ambient temperature. The mixture was then stirred for a further 2 h at 50 ° C before being poured into water (1.5 L). The resulting solution was filtered through celite, and sodium 79323 bicarbonate was then added to the filtrate until no more precipitation occurred.

The precipitate was collected and crystallized from methanol-water to give the title product as yellow prismatic crystals (19.4 g, 56%), m.p. 165.1 ° C.

Δ IR: 3400, 3280 (NH-), 2220 (CN), 1640, 1540, 1460 -1 Δ and 815 cm

Elemental analysis for C ^ qH ^ N ^ S:

Calculated: C 59.09%; H 4.46%; N 20.67%, S 15.77% Found: C 58.76%; H 4.42%; N 20.74%, S 15.74% Step B: Ethyl (2-amino-oC-methylbenzothiazole-6-acetate

A solution of 95% ethanol (10 ml), concentrated 1 H 2 SO 4 (10 g) and the compound prepared in Step A above (0.5 g) and stirred was refluxed for 15 h. The mixture was then cooled and diluted with water and the ethanol was evaporated off. The resulting solution was neutralized with sodium hydrogen carbonate to give a solid which was collected and recrystallized from methanol-water to give the title compound as yellowish needle-like crystals (0.38 g, 61%), m.p. 146 ° C.

IR: 3370, 3120, 2980, 1710 (ester-CO), 1640, nix m 1540, 1470, 1375, 1330, 1295 and 1225 cm-1

Elemental analysis for C 12 H 14 N 2 O 2 S: 25 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% The ethyl (2-amino-1'-methylbenzothiazole-6-acetate) used as starting material can also be prepared as follows: Ethyl 2- (p-aminophenyl) propionate-154.5 g; Arzneim Forsch 23 (1973) 10907 was dissolved in 95% acetic acid, and potassium isothiocyanate (261 g) was added to the solution with stirring, followed by the dropwise addition of a solution containing 0 : 3 (149.4 g) in 95% acetic acid (750 ml) The mixture was stirred for a further half hour, after which it was poured into water (8 L), the mixture was filtered through celite and the pH of the filtrate was then adjusted to 5-6. Using a 2% Na 2 CO 2 solution (more than 6 L), the product was then extracted into CH 2 Cl 2, and the organic layer was separated, washed with water, dried over MgSO 4 and finally filtered and evaporated. (300 ml) and an equal volume of petroleum ether (40-60 ° C) was added. Cream-colored crystals which were filtered off were washed with ethyl acetate-petroleum ether and dried to give the product (97 g, yield 48.5%), m.p. 146 ° C. A second crop (29 g) of product was obtained from the mother liquors. The overall yield was 63%.

Example 3: Ethyl (2-oxo-4-phenyl-2H-pyrimido) -2,2-benzothiazole-8-acetate

A mixture of ethyl (2-aminobenzothiazole-6-acetate) (5 g) and ethyl (phenylpropiolate) (6 g) and stirred was heated in an oil bath at 200 ° C for 1 h. The crude mixture was then purified on a column (200 g). 20 silica gel) using CHCl 3 and eluent. The product obtained was brightly colored and crystallized from CHCl 3 and recrystallized from ethanol to give ethyl (2-oxo-4-phenyl-2H-pyrimido / 2,1-27-benzothiazole-8-acetate) as orange plate-like crystals (1.99 g, yield 26%).

Example 4: Methyl (2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate)

Using a procedure similar to Example 1 but starting from a similar compound of formula II wherein R 1 'is a methoxyl group and ethyl (phenylpropiolate) (compound of formula III), the desired compound was obtained.

Example 5: n-propyl (2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate)

The desired compound was obtained using a procedure similar to Example 3 but starting from a similar compound of formula II, i7 79323 wherein R.j 'is an n-propoxyl group, and ethyl (phenylpropiolate) (compound of formula III).

Example 6: Isopropyl (2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate) The title compound was obtained using a similar procedure to Example 3 but starting from a similar compound of formula II wherein 'is an isopropoxyl group, and ethyl (phenylpropiolate) (compound of formula III).

Example 7: n-Butyl (2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate)

The desired compound was obtained using a similar procedure to Example 3 but starting from a similar compound of formula II wherein R 1 is an n-butoxyl group and ethyl (phenylpropiolate) (compound of formula III).

Example 8: 2-Oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetic acid

A mixture of ethyl (2-oxo-4-phenyl-2H-20-pyrimido / 2,1-benzoylthiazole-8-acetate) (compound prepared in Example 3; 2.47 g), methanol (100 ml) and aqueous potassium carbonate solution ( 2.47 g in 20 ml), was stirred at ambient temperature overnight. The methanol was evaporated off and the residue was diluted with water and then acidified with concentrated HCl. The precipitate was collected, dried and then recrystallized twice from methanol to give 2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetic acid as yellow plate-like crystals (1.72 g, yield 75 %).

30 Examples 9-19

Using a procedure similar to that of Example 3 but starting from ethyl (2-aminobenzothiazole-6-acetate) of formula II and compounds of formula III wherein R 2 has the meanings given in Table 1 below and R 1 represents: ethyl group, the following compounds were prepared; is 79323

Example 9: Ethyl 4- (4-methoxyphenyl) -2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate7;

Example 10: Ethyl 4- (4-nitrophenyl) -2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate7; Example 11: Ethyl 4- (4-chlorophenyl) -2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate7;

Example 12: Ethyl 4- (2-chlorophenyl) -2-oxo-2H-pyrimido [2,1-h] benzothiazole-8-acetate7;

Example 13: Ethyl 4- (4-methylphenyl) -2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate];

Example 14: Ethyl 4- (3-chlorophenyl) -2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate7;

Example 15: Ethyl (4-methyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate); Example 16: Ethyl (4-ethyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate);

Example 17: Ethyl (2-oxo-4-n-propyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate);

Example 18: Ethyl (4-n-butyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate); and

Example 19: Ethyl (4-methoxycarbonyl-2-oxo-2H-pyrimido [5,1-b] benzothiazole-8-acetate).

Example 20: Ethyl (?-Methyl-2-oxo-4-phenyl-2H-pyrimido / 2,1-benzoylthiazole-8-acetate) A mixture of ethyl (2-amino-eO-methylbenzothiazole-6- acetate) (50 g) and ethyl (phenylpropylate) (34.9 g) were heated in an oil bath at 100 ° C with stirring for 20 h, after which time a further 7 g of ethyl (phenylpropiolate) was added. Heating was continued for a further 96 h, after which time the reaction was 93% complete by HPLC. Ether (500 ml) was then carefully added, and the mixture was refluxed with stirring for 2 h. Ethyl (oC-methyl-2-oxo-4-phenyl-2H-pyrimido [1,1-b] benz-35-sothiazole-8- acetate) and the solution was cooled. The crystalline product thus obtained was filtered off, washed with ether and dried to give ethyl (* - methyl-2-oxo-4-phenyl-2H-pyrimido / * 2,1-tert-benzothiazole-8-acetate). ) (39 g, 51% yield), 99.9% purity by HPLC, m.p. 127-131 ° C.

Ethyl (2-amino-β-methylbenzothiazole-6-acetate) was prepared as described in Example 2.

Example 21: 1 H -methyl-2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-e-acetic acid

The desired compound was obtained using a similar method of Melo as in Example 8 but starting from the ethyl prepared in Example 20 (ci-methyl-2-oxo-4-phenyl-2H-pyrimido / 2,1-benzothiazole-8-acetate).

Examples 22-24

A procedure similar to that of Example 8, but using ethyl (2-amino-10-methylbenzothiazole-6-acetate) and compounds of formula III as starting materials, wherein 1 * 2 has the meanings given in Table 1 below and means ethyl group, the following compounds were prepared: Example 22: Ethyl 4-methyl-4- (4-chlorophenyl) -2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate7;

Example 23: Ethyl N-methyl-4- (3-chlorophenyl) -2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate; and

Example 24: Ethyl N-methyl-2-oxo-4-n-propyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate).

Examples 25-43

Using the same procedures as above and using the appropriate compounds of formulas II and III as starting materials, the following compounds were 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);

Example 27: Ethyl (o-methyl-4-benzyl-2-oxo-2H-pyrimido [5,1-b] benzothiazole-8-acetate); 20 7 9 3 2 3

Example 28: Ethyl (N, N-methyl-4-isopropyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate);

Example 29: Ethyl (n-ethyl-4-phenyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate); Example 30: Ethyl (4-cyclohexyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate);

Example 31: Ethyl (? -Methyl-4-cyclohexyl-2-oxo-2H-pyrimido [2,1-n] benzothiazole-8-acetate);

Example 32: Ethyl (α-propyl-4-phenyl-2-oxo-2H-pyrimido-2,1-b] benzothiazole-8-acetate);

Example 33: Ethyl (cis-isopropyl-4-phenyl-2-oxo-2H-pyrimido [2,1-a] benzothiazole-8-acetate);

Example 34: Ethyl («6-butyl-4-phenyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate); Example 35: Isopropyl (o (.-Methyl-4-phenyl-2-oxo-2H-pyrimido / 2,1-b [7-benzothiazole-8-acetate));

Example 36: Ethyl (ol, ol-dimethyl-4-phenyl-2-oxo-2H-pyrimido [1,2-b] benzothiazole-8-acetate);

Example 37: Ethyl (N-ethyl-α-methyl-4-phenyl-2-oxo-2H-pyrimido [2,1-c] benzothiazole-8-acetate);

Example 38: Ethyl (ol-methyl-1'-propyl-4-phenyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate);

Example 39: t-butyl (α-methyl-4-phenyl-2-oxo-2H-pyrimido / '2,1-H] benzothiazole-e-acetate); Example 40: Ethyl (o, N-diethyl-4-phenyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate);

Example 41: Ethyl (N-ethyl-cis-propyl-4-phenyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-e-acetate);

Example 42: Ethyl (4-butyl-α-methyl-4-phenyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate); and

Example 43: 2,2-Dimethylpropyl (o -, - methyl-4-phenyl-2-oxo-2H-pyrimido [2,1-b] benzothiazole-8-acetate).

Example 44: N, N-Dimethyl-2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetamide 35 g of 2-oxo-4-phenyl-2H-pyrimido-2.1 β-Benzothiazole-8-acetic acid was dissolved in tetrahydrofuran (40 ml), and 1,1'-carbonyldiimidazole (2 g) was added to the solution.

21 79323

The mixture was stirred at room temperature for 1 h until dissolution occurred. Excess dimethylamine (30% in EtOH) was added and the mixture was stirred for an additional 40 min. The THF was then removed under reduced pressure and the residue was dissolved in dichloromethane, washed with water, bicarbonate solution and water, dried (MgSO 4), filtered and evaporated. A pale brown-yellow solid was obtained which was purified by flash chromatography on silica gel. The yield was 1.1 g and the melting point was 238-240 ° C.

Examples 45-48

Using methods similar to above and using the appropriate amine as starting material, the following compounds were prepared:

Example 45: N-ethyl-2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetamide;

Example 46: 1- (N-morpholino) -2- (2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazol-8-yl) ethanone;

Example 47: N, N-Diethyl-2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetamide; and Example 48: 1- (N-Piperidino) -2- (2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazol-8-yl) ethanone.

22 79323

table 1

Example R R 1 R 2 R 3 Sp. (° C) 1 H EtO HH 276 2 Me EtO HH 129 3 H EtO Ph H 206 4 H MeO Ph H 225-6 5 H nPrO Ph H 133.5- H 134.5 6 H isoPrO Ph H 171.5- 172.5 7 H nBuO Ph H 136-7 8 H HO Ph H decomposes slightly at 136 ° C, melts at 25 ° C 9 H EtO g-MeOPh H 152 10 H EtO o-NO 2 Ph H 246 11 H EtO D-ClPh H 220. : 12 H EtO o-ClPh H 196.5 13 H EtO p-MePh H 133-4; * 14 H EtO m-ClPh H 176-9: 15 H EtO Me H 251-3 16 H EtO Et H 166.7 : 17 H EtO nPr H 158-60 18 H EtO nBu H 149.6 19 H EtO C02Me H 163 20 Me EtO Ph H 127-31 21 Me HO Ph H 239-46 22 Me EtO p-ClPh H 190-1 23 Me EtO m-ClPh H 76-9 24 Me EtO nPr H 125-6 23 79323

Table 1 (continued)

Example R R 1 R 2 R 3 Sp. (° C) 25 H EtO isoPr H 170-2 26 H EtO CH2Ph H 197-9 27 Me EtO CH2? H 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 126-3 34 3u EtO Ph H 92-94 35 Me i so P r O Ph H 15 3-5 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 133-40: -: 41 Et EtO Ph Pr 163 -4 42 Me EtO Ph Bu 143-4: 43 Me t-BuCH 2 O Ph H 122-3

Il 44 H Me2N Ph H 238-40 45 H EtHN Ph H 210-2 46 H O \ ϊ Ph H 214-6 47 H Et2N Ph H 147-9 48 H C N Ph H 190-1 24 79323

Table 1 (continued)

calculated

Example Formula% C% HN% S% 1. , 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 3r7 10.25 7.35 11 C20H15N2 ° 3Cl1 60.2 3.8 7.0 8.05 12 C20H15N2 ° 3Cl1 60 , 2 3.8 7.0 8; 05 13 C21H18N2O3S 66.65 4.8 7.4 8.45 14 C20H15N2O3Cl1S 60.2 3P8 7.0 8.05 15 C15H14N2 ° 3S 59r6 4; 65 9; 25 10.6: 16 C16H16N2 ° 3S 60.75 5.1 8.85 10.15 / 17 C17H18N2 ° 3S 61.8 5.5 3.5 9.7 18 C18H20N2 ° 3S 62.75 5.85 8.15 9.3 19 C16H14N2 ° 5S S5r5 V05 8.19; 25 20 C21H18N2 ° 3S 66 ^ 65 4.8 7.4 8.45 21 C19H14N2 ° 3S 66 ^ 15 4.05 8.0 9f15 22 C21H17N2 ° 3Cl1 61JL 4.15 6 , 8 7/75 23 C 21 H 17 N 2 O 3 Cl 1 S 61.1 4.15 6.8 7.75 24 C 18 H 20 N 2 O 3 S 62.75 5.85 8.15 9.3 25 79323

Table 1 (continued)

calculated

Example Formula * c% HN% S% 25 C17H18N2O3S 61.80 5.49 3f 489 f 7 0 26 G21H18N2 ° 3S 66765 4.79 7.40 8.47 27 C22H'50N2O3S'1 / 2H2O 65.82 5; 27 6.98 7-99 23 C 18 H 20 N 2 O 3 S 62; 7 7 5.85 3; 13 9.29 29 C22H20N2 ° 3S 67 7 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 3; 34 32 C23H22N2O3S 67.96 5.46 6.39 7.39 33 C23H22N2O3S.1 / 2H2O 66.49 5.58 6.74 7.72 34 C24I24N2 ° 3S 68.55 5, 75 6.66 7.62 35 C, 2H 2 N 2 O 3 S 67.33 5.14 7.14 3.17 36 C 22 H 20 N 2 O 3 S 67.33 5.14 7.14 9.17 37 C 23 H 22 N 2 O 3 S 67 .96 5.46 6.39 7, S9 33 Co.H_, M ~ 0, S 68.55 5.75 6.56 7.62 39 C23H22N2O3S 67.96 5.46 6.89 7.89 40 C24H24N2O3S 68.55 5, 75 6.66 7.62 / 41 C25H26N2O3S 69.10 6.03 6.45 7.38 / V 42 C25H26N2O3S 69.10 6.03 6.45 7.38: 43 C24H24N2 ° 3S 68.55 5.75 6.66 7.62 44 C20H17N3O2S * 1 / 2H2 ° 64.50 4.87 11.28 8.61 45 C20H17N3 ° 2S * 1 / 2H2 ° 64.50 4.87 11.28 8r61 46 C22H1qN301S. 1 / 2H70 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 26 79323

Table 1 (continued)

The resulting

Example% C% H% N SS

1 58.25 4.25 9.7 5 11.1 2 59.5 4.6 5 9, 3 10.45 3 66, 2 4.5 7.65 8.35 4 - 5 66.55 4.85 7.35 8.35 6 66.65 4.85 7.4 3.45 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 3 , 2 10 58.6 3.75 10.25 7.3 11 60.15 3.85 6.95 3.05 12 60.25 3.9 7.0 3.1 13 66 r 45 4.85 7.40 3.6 14 60, 25 3.9 7.05 3.1 15 59.6 4.7 9 r 3 10.5 5 16 60.5 5 r 1 8.8 10.15 17 61.7 5.5 8.45 9.75 13 62.5 5.9 8.15 9.45; 19 55.3 4.15 8.0 9.15 20 66.5 4.85 7.45 3.4 21 64.9 4.05 8r0 9.1 22 61.1 4.25 6.75 7.75 23 60.85 4.3 6.75 7.35 24 62.65 5.85 3.15 9.3 27 7 9 3 2 3

Table 1 (continued)

The resulting

Example% C% H% N% S

25 61.88 5.51 3f51 9.64 26 66.55 4.85 7.37 3.43 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 3.12 30 64.85 5.95 7.62 3.64 31 65.62 6.34 7.21 3.35 32 67.84 5.54 6.35 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 6.57 7.59 38 68.30 5.36 6.54 7.53 39 68 T 10 5.50 6.84 7.37 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 7T28 43 68.62 5 ^ 78 6.65 7.63 44 64.50 4.72 11.18 3 , 54 45 64.46 4.71 11.28 8.52 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

Claims (5)

28 7 9 3 2 3 A process for the preparation of novel therapeutically useful pyrimidoZ2,1-b / benzothiazoles of the formula (I) and their salts, R2 = ^ / - \ = 0 R 1 (R 11) wherein R and R 1, which may be the same or different, each represent a hydrogen atom or a straight-chain or branched C 1-6 alkyl group; R 1 represents a hydroxy group, a straight-chain or branched C 1-6 alkoxy group or a group -N (A) in which R 1 is. and R 9, which may be the same or different from the central R 6, each represent a hydrogen atom or a C 1-8 alkyl group, or together with an intervening nitrogen atom form a piperidino or morpholino group; and R 2 represents a hydrogen atom or a straight-chain or branched C 1-8 alkyl, C 2-7 alkoxycarbonyl or C 2-8 cycloalkyl group, a phenyl, alkylphenyl, alkoxyphenyl, halophenyl, nitrophenyl or benzyl group, known therefrom, II) compound 30 ^ NR (if \ - \ l, J1) -m2 (II) 35. COR' ± wherein R and R3 are as defined above and R3 'represents a C1-8 alkoxy group, is reacted with a compound of formula (III) wherein 292323 r2-c = c-co2r4 (III) wherein R2 is as defined above and R 1 represents an alkyl group to give a compound of formula (Ia), R 2, v 15 r 3 I COR '1 wherein R, R 2, R 2' and R 2 are as defined above, followed, if desired, by saponification of the compound of formula (IA) to give a compound of formula (Ιβ), R 0 0. X: v ° COOH wherein R, R 3 and R 2 are as defined above, and then, if desired, reacting a compound of formula (Ιβ) with a compound of formula 35 ^ R 5 mr 30 79323 wherein Rg and Rg are as defined above, to give a compound of formula I wherein R 1 is R 6, after which the compounds thus obtained are isolated and, if desired, their salts are formed by conventional methods. Process according to Claim 1, characterized in that ethyl (2-oxo-4-phenyl-2H-pyrimido [2,1-b] benzothiazole-8-acetate) is prepared; ethyl 2-oxo-4- (p-methoxyphenyl) -2H-pyrimido [2,1-b] benzothiazole-8-acetate; £ ethyl 2-oxo-4- (o-chlorophenyl) -2H-pyrimido £ 2, £ L / sotiatsoli-benzyl-8-asetaatti7; 15 ethyl N-methyl-2-oxo-4-phenyl-2H-pyrimido [1,1-b] benzothiazole-8-acetate; Ethyl 7 - ((methyl-2-oxo-4- (p-chlorophenyl) -2H-pyrimido-1,2,1-benzothiazole-8-acetate) or ethyl (N-ethyl-2-oxo-4-phenyl) -2H-pyrimido [2,1-e] benzo-20-thiazole-8-acetate) or a salt thereof.