MXPA00007623A - Benzothiadiazoles and derivatives - Google Patents

Abstract

The invention provides a compound of formula (I) wherein X, R1, R2 and Het are as defined in the description, and a process for preparing them. The compounds of formula (I) are useful as pharmaceuticals.

Description

BENZOTIADIAZOLES AND DERIVATIVES The present invention relates to novel benzothiadiazoles and their derivatives, to their preparation, to their use as pharmaceuticals, and to pharmaceutical compositions containing them. t. In a more particular manner, the invention provides a compound of Formula I: wherein: X is 0, S, N-CH3, CH = CH or CAlk = CAlk, wherein Alk is independently alkyl (of 1 to 4 carbon atoms),. Ei and E2 are independently hydrogen, halogen, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), or trifluoromethyl, and Het is a radical having one of the formulas (a) to (a) p) following: (0 (b) (c) (d) (i) 0) (k) (1) (m) 00 (o) (P) wherein: R3 and R8 are independently hydrogen or alkyl (from 1 to 4 carbon atoms), R 4 is hydrogen, halogen, alkyl (from 1 to 4 carbon atoms), cyano, nitro, formyl or alkylcarbonyl (from 1 to 4 carbon atoms), Rs and Rβ are independently hydrogen, alkyl (from 1 to 7 carbon atoms), alkenyl (from 3 to 7 carbon atoms), cycloalkyl (from 3 to 7 carbon atoms), cycloalkyl (from 3 to 7 carbon atoms) -alkyl (from 1 to 4) carbon atoms), alkoxy (of 1 to 4 carbon atoms) -alkyl (of 2 to 5 carbon atoms) or benzyl, R7 is hydrogen, hydroxyl, alkyl (of 1 to 4 carbon atoms, or alkoxy (of 1 to 4 carbon atoms), W is N, C-CN, CN 02, C-COH or C-CO-Alk, wherein Alk is as defined above, and X is as defined above, in the form of free base or acid addition salt. Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. The radical Het is preferably located on a carbon atom that is adjacent to the heterocyclic moiety in Formula I. Preferably, Het is of the formulas (a) a (k), particularly of formula (a). In a further aspect, the invention provides a process "for the production of the compounds of Formula I and their salts, wherein a compound of Formula II is reacted: wherein X, Ri and R2 are as defined above, and Y is a radical having one of the following formulas (a ') to (p'): (»R 0» (c (d) ((O (ti (M m W (k) m wherein R3 to Rs, W and X are as defined above, and Hal is halogen, with a compound of formula III: R * / HN. m \ R. wherein R5 and Re are as defined above, and the resulting compound is recovered as a free base or as an acid addition salt. The reaction can be carried out in a known manner, for example, as described in Example 1. Hal is preferably chlorine, bromine or iodine, particularly chlorine. The work of the reaction mixtures obtained according to the above process, and the purification of the compounds thus obtained, can be carried out according to the known procedures. Acid addition salts can be produced in a known manner, from the free base forms and vice versa. The pharmaceutically acceptable acid addition salts suitable for use in accordance with the present invention include, for example, the hydrochloride, the acid maleate, the acid fumarate, and the acid malonate. "The starting materials of Formula II can be obtained as follows: Compounds of Formula II can be obtained, wherein Y is a radical having one of the formulas (a ') and (d'), by the reaction of a compound of Formula IV: wherein X, Ri and R2 are as defined above, with a compound of the Formula Va or Vd: Go Vd where R3 and R4 are as defined above, and Hal is independently halogen. Compounds of Formula II can be obtained, wherein Y is a radical having one of the formulas (b '), (c') and (e ') to (1'), by the reaction of P0C13, with a compound of Formula VI: where Yf is a radical having one of the following formulas (b "), (c"), and (e ") to (1"): ib ") (e") (f) O ") Oc") 0") wherein R3, R, R7, Rs and are as defined above. All the aforementioned reactions are conventional. The compounds of Formulas III, IV, Va, Vd and VI are known or can be obtained from known compounds, using conventional methods. the compounds of Formula I, and their pharmaceutically acceptable acid addition salts, referred to hereinbelow as agents of the invention, exhibit valuable pharmacological properties when tested in vitro using cell cultures that express the corticotropin releasing factor receptor. (CRF), and in animals, and therefore, are useful as pharmaceuticals ^. In particular, the agents of the invention bind to corticotropin releasing factor receptors.

More particularly, they exhibit an antagonistic activity at CRFi receptors, as determined in vi tro in the following assay: Chinese hamster ovary (CHO) cells expressing human recombinant CRF are propagated (Chen et al., Proc Nati Acad Sci USA 90, 8967-8971, 1993) in an Eagle's medium modified by Dulbecco, supplemented with fetal calf serum at 10 percent, non-essential amino acids, 100 units / milliliter of penicillin, 100 milligrams / liter of streptomycin, and 1 gram / liter of geneticin (G418). For determinations of cyclic AMP, cells are grown to confluence in 24-well plates. Stimulation of cyclic AMP accumulation by corticotrspin release factor (human / rat form) is measured in intact cells using the [3 H] adenine labeling technique, as previously described (Schoeffter et al., Neuropharmacology 36, 429-437, 1997). Concentration-response curves are constructed for the corticotropin release factor in the presence of putative antagonists (10 M) or vehicle (dimethyl sulfoxide at 1 volume percent).

The KB values are calculated from the changes to the right of the control curve, according to the formula: KB = [antagonist, M] / concentration ratio-1), where the concentration ratio designates the ratio of the EC50 value of the corticotropin release factor in the presence / EC50 value of the corticotropin releasing factor in the presence / EC50 value of the corticotropin release factor in the absence of the antagonist [Furchgott, in: Catecholamines (edited by Blaschko H and Muscholl E), pages 283-335, Springer, Berlin, 1972]. In this test, the agents of the invention show an antagonist activity of CRFX with Kb CRFi values of approximately 1 to 500 nM. The agents according to the invention, therefore, are useful in the treatment of any condition with an increased endogenous level of the corticotropin releasing factor, or where the HPA (hypothalamic pituitary axis) is deregulated, or of different induced diseases. facilitated by the corticotropin releasing factor, including inflammatory disorders, such as arthritis, asthma and allergies; anxiety, including generalized anxiety; phobic and panic attacks; depression; fatigue syndrome; headache; pain, for example, inflammatory or neuropathic pain; Cancer; Irritable bowel syndrome, including Crohn's disease, spastic colon and irritable color; immune dysfunction; infections by human immunodeficiency virus (HIV); neurodegenerative diseases, such as senile dementia, Alzheimer's disease and Parkinson's disease; embolism and head trauma; epilepsy; gastrointestinal diseases; disorders in eating and in body weight, such as obesity and anorexia nervosa; hemorrhagic tension; withdrawal symptoms of drugs and alcohol; drug addiction, sleep disorders; hormonal dysregulations; skin disorders; psychotic episodes induced by tension; Fertility problems; sexual dysfunctions and premature birth. The utility of the agents of the invention in the aforementioned diseases could be confirmed in a range "of conventional tests: For example, the anxiolytic activity of the agents of the invention could be confirmed in high mouse obfuscation [see, for example, Rodgers, RJ, Behavioral Pharmacology 8: 477-496 (1997), where the relevance of high obfuscation is discussed on page 486; for the method, see Rodgers RJ et al., Ethology and Psychopharmacology (Eds SJ Cooper and CA Hendrie ), pages 9-44 (1994), J. Wiley, Chichester.] In this test, the agents of the invention show anxiolytic-like effects after administration of 0.1 to 30 milligrams / kilogram orally. the appropriate dosage will, of course, vary depending on, for example, the compound employed, the host, the mode of administration, and the nature and severity of the condition that is being treated. However, it is generally indicated that satisfactory results are obtained in animals with a daily dosage of from about 0.1 to about 100, preferably from about 0.5 to about 100 milligrams / kilogram of body weight of the animal. In larger mammals, for example, humans, an indicated daily dosage is in the range of from about 1 to about 500, preferably from about 1 to about 300 milligrams of an agent of the invention, conveniently administered, for example, in doses divided up to four times a day, or in a sustained release form. The agent of the invention can be administered by any conventional route, in particular enterally, preferably orally, for example, in the form of tablets or capsules, or parenterally, for example, in the form of injectable solutions or suspensions. For the aforementioned indications, a preferred compound is the compound of Example 1 described below. In the binding test described above, this compound exhibits a CRFi antagonist activity, with a Kb CRFi of 36 nM. In the high obfuscation described above, doses of 0.1 to 10 milligrams / kilogram (with a maximum of 3 milligrams / kilogram), significantly affect the behavioral parameters related to anxiety. In contrast to the chlorodiazepide standard, the parameters related to the motor stimulus are not affected, which indicates that the observed anxiolytic effects can not be attributed to a general motor stimulus.

In accordance with the above, the present invention also provides an agent of the invention, to be used as a pharmaceutical product, for example, for the treatment of induced diseases. or facilitated by the corticotropin release factor, such as those indicated above. In addition, the present invention provides a pharmaceutical composition comprising an agent of the invention in association with at least one pharmaceutical carrier or diluent. These compositions can be manufactured in a conventional manner. The unit dosage forms contain, for example, from about 0.25 to about 150, preferably from 0.25 to about 25 milligrams of a compound according to the invention. Moreover, the present invention provides the use of an agent of the invention, for the manufacture of a medicament for the treatment of any condition mentioned above. In yet a further aspect, the present invention provides a method for the treatment of any condition mentioned above, in a subject in need of such treatment, which comprises administering to this subject a therapeutically effective amount of an agent of the invention. The following examples illustrate the invention. Temperatures are given in degrees Celsius, and are not corrected.

Example 1; 5, 7-dimethyl-4 [2,5-dimethyl-6- (di-n-propyl) -amino-p? Rimidin-4-yl] -amino-2,3,1-benzothiadiazole A solution of 4- ( 4-chloro-2, 5-dimethyl-pyrimidin-6-yl) -amino-5,7-dimethyl-2,3,1-benzothiadiazole (3.5 grams) and amine di-n-propylamine (5.35 milliliters) in n- absolute methylpyrrolidone (35 milliliters), is stirred at 157 ° C in a sealed container for 96 hours. The reaction is monitored using thin layer chromatography. The reaction mixture is cooled, 50 milliliters of water are added, and the aqueous phase is extracted twice with methyl-t-butyl ether (2 × 200 milliliters). The organic phase is dried, evaporated, and chromatographically separated on silica gel, using cyclohexane / methyl-t-butyl ether. (5: 1) The appropriate fraction is evaporated, and the residue is recrystallized from methanol, to give the title product. P.f. = 117-119 ° C. The starting material, 4- (4-chloro-2,5-dimethyl-pyrimidin-6-yl) -amino-5,7-dimethyl-2,3,1-benzothiadiazole, is produced as follows: Dissolve 4, 6-dimethyl-2,3,1-benzothiadiazole (7.7 grams) in concentrated sulfuric acid (20 milliliters), cooled with stirring at 0.5 ° C, and nitric acid (2.5 milliliters, d = 1.52) is added dropwise. The clear solution is poured onto ice, the precipitate thus obtained is filtered, and washed with water. The resulting 5,7-dimethyl-4-nitro-2, 1, 3-benzothiadiazole is recrystallized from cyclohexane. P.f. = 105-106 ° C. The 5,7-dimethyl-4-nitro-2, 1, 3-benzothiadiazole (20 grams) is heated to boiling in water (2.2 liters) and ethanol (2.2 liters), and sodium dition ta is added in portions. (strongly exothermic reaction). The reaction mixture is immediately cooled in an ice bath, and extracted with ethyl acetate. The organic phase is concentrated by evaporation, and the residue is recrystallized from water to give 4-amino-5,7-dimethyl-2, 1,3-benzothiadiazole. P.f. = 113-114 ° C. 4-Amino-5,7-dimethyl-2,3,1-benzothiadiazole (4 grams) is added in portions to a 55 percent dispersion of sodium hydride (2.72 grams) in absolute tetrahydrofuran (50 milliliters) under a argon atmosphere. The mixture is stirred -30 ° C for 3 hours, then a solution of 4,5-dichloro-2,5-dimethyl-pyrimidine (4 grams) in absolute tetrahydrofuran (20 milliliters) is added dropwise at 5 ° C for 30 minutes. The reaction mixture is stirred at room temperature for an additional 16 hours, and then ice water is carefully added.

The resulting precipitate is washed with water and a little methanol.

After recrystallization from methanol or cyclohexane, 4- (4-chloro-2,5-dimethyl-pyrimidin-6-yl) -amino-5,7,7-dimethyl-2,3,1-benzothiadiazole is obtained. P.f. = 174-177 ° C. The following compounds of Formula I are prepared in a manner analogous to Example 1: a) Compounds of the Formula: Me = Methyl; Et = ethyl; *: Fumarate b) Compounds of the Formula: Me = Methyl; Et = Ethyl c) Compounds of the Formula: Me = Methyl; Et = Ethyl d) Compounds of the Formula: Me = Methyl; Et = Ethyl e) Compounds of the Formula: Me = Methyl; Et = Ethyl f) The compound of the formula: Me Methyl; *: Fumarate

Claims (9)

1. CLAIMS A compound of Formula I: eh where: X is 0, S, N-CH3, CH = CH or CAlk = CAlk, wherein Alk is independently alkyl (of 1 to 4 carbon atoms), Ri and 2 are independently hydrogen, halogen, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), or trifluoromethyl, and Het is a radical having one of the following formulas (a) to (p); (0 (g) (h) wherein: R3 and Rs are independently hydrogen or alkyl (from 1 to 4 carbon atoms), R is hydrogen, alkyl (from 1 to 4 carbon atoms), cyano, nitro, "formyl or alkylcarbonyl (from 1 to 4 carbon atoms), R5 and ß are independently hydrogen, alkyl ( from 1 to 7 carbon atoms), alkenyl (from 3 to 7 carbon atoms), cycloalkyl (from 3 to 7 carbon atoms), cycloalkyl (from 3 to 7 carbon atoms) -alkyl (from 1 to 4 carbon atoms ), alkoxy (of 1 to 4 carbon atoms) -alkyl (of 2 to 5 carbon atoms) or benzyl, R7 is hydrogen, hydroxyl, alkyl (of 1 to 4 carbon atoms, or alkoxy (of 1 to 4 atoms) carbon), W is N, C-CN, C-N02, C-COH or C-CO-Alk, wherein Alk is as defined above, and t X, is as defined above, in the form of free base or of acid addition salt 2. "5, 7-Dimethyl-4- [2,5-dimethyl-6- [di-n-propyl] -amino-pyrimidin-4-yl] amino-2, 1, 3 -benzothiadiazole in the form of free base or acid addition salt 3. A process for the preparation of a compound of Formula I as defined in claim 1, or a salt thereof, which includes the step of making reacting a compound of Formula II: wherein * X, R1 and R2 are as defined in claim 1, and Y is a radical having one of the following formulas (a ') to (p "): OO (b) (< 0 (d) (i) (i) (k) < n wherein R3 to R8, W and X are as defined in claim 1, and Hal is halogen, with a compound of the formula III: R. / HN. m \ wherein R5 and R6 are as defined in claim 1, and recovering the compound thus obtained of Formula I in the form of free base or acid addition salt. 4. A compound of claim 1 or 2, in the form of free base or pharmaceutically acceptable acid addition salt, for use as a pharmaceutical product. 5. A compound of claim 1 or 2, in the form of a free base or pharmaceutically acceptable acid addition salt, for use in the treatment of any condition with an increased endogenous level of the corticotropin releasing factor, or where deregulate the hypothalamic pituitary axis, or of a disease induced or facilitated by the corticotropin release factor. 6. A pharmaceutical composition comprising a compound of claim 1 or 2, in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. The use of a compound of claim 1 or 2, in the form of a free base or pharmaceutically acceptable acid addition salt, as a pharmaceutical product for the treatment of any condition with an increased endogenous level of the corticotropin releasing factor. , or where the pituitary hypothalamic axis is deregulated, or of a disease induced or facilitated by the corticotropin release factor. The use of a compound of claim 1 or 2, in the form of a free base or pharmaceutically acceptable acid addition salt, for the manufacture of a medicament for the treatment of any condition with an increased endogenous level of the release factor of corticotropin, or where the hypothalamic pituitary axis is deregulated, or of a disease induced or facilitated by the corticotropin release factor. 9. A method for the treatment of any condition with an increased endogenous level of the corticotropin releasing factor, or wherein the hypothalamic pituitary axis is deregulated, or of a disease induced or facilitated by the corticotropin releasing factor, in a subject in need of such treatment, which comprises administering to this subject a therapeutically effective amount of a compound of claim 1 or 2, in free base or pharmaceutically acceptable acid addition salt form.