Oxytocin receptor agonists for the treatment of CNS diseases

Abstract

The invention relates to the use of a compound of formula I ##STR00001##
wherein A.sup.1 is phenyl or a five or six membered hereroaryl group, containing 1, 2 or 3 heteroatoms, selected from N or S; R.sup.1 is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen or cycloalkyl; A.sup.2 is phenyl; R.sup.2 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano, S-lower alkyl substituted by halogen, S(O).sub.2-lower alkyl substituted by halogen; n is 1 or 2;
or a pharmaceutically acceptable acid addition salt, or a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, for the treatment of autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, psychiatric disorders and memory loss, alcohol withdrawal, drug addiction and for the treatment of Prader-Willi Syndrome.

Claims

1. A method of treating a condition selected from the group consisting of autism, stress, post traumatic stress disorder, anxiety disorders, depression, schizophrenia, psychiatric disorders, memory loss, alcohol withdrawal, drug addiction and Prader-Willi Syndrome, comprising administering a compound of formula I ##STR00034## wherein A.sup.1 is phenyl or a five or six membered heteroaryl group, containing 1, 2 or 3 heteroatoms, selected from N or S; R.sup.1 is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen or cycloalkyl; A.sup.2 is phenyl; R.sup.2 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano, S-lower alkyl substituted by halogen, S(O).sub.2-lower alkyl substituted by halogen; n is 1 or 2; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, to a patient in need thereof.

2. A method of treating a condition selected from the group consisting of autism, stress, post traumatic stress disorder, anxiety disorders, depression, schizophrenia, psychiatric disorders, memory loss, alcohol withdrawal, drug addiction and Prader-Willi Syndrome, comprising administering a compound selected from the group consisting of 4-Chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide 4-Ethyl-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide 4-Propyl-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide 2-Chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide 4-Difluoromethoxy-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide 4-Chloro-N-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-benzenesulfonamide 4-Cyano-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide N-[2-(4-Methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide 4-Chloro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide 4-Ethyl-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide N-(2-Pyrimidin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide 2,4-Dichloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide 4-Chloro-2-fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide 4-(1-Fluoro-ethyl)-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide N-[2-(4-Methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide 4-Chloro-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide 4-Ethyl-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide 4-Cyano-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethylsulfanyl-benzenesulfonamide 4-Trifluoromethyl-N-[2-(2-trifluoromethyl-pyrimidin-4-yl)-2H-pyrazol-3-yl]-benzenesulfonamide 2-Fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethanesulfonyl-benzenesulfonamide 3-Fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide N-[2-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-2H-pyrazol-3-yl]-4-ethyl-benzenesulfonamide and 4-Chloro-2-fluoro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide to a patient in need thereof.

3. A pharmaceutical composition comprising a compound selected from the group consisting of 4-Chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide 4-Ethyl-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide 4-Propyl-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide 2-Chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide 4-Difluoromethoxy-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide 4-Chloro-N-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-benzenesulfonamide 4-Cyano-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide N-[2-(4-Methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide 4-Chloro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide 4-Ethyl-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide N-(2-Pyrimidin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide 2,4-Dichloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide 4-Chloro-2-fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide 4-(1-Fluoro-ethyl)-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide N-[2-(4-Methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide 4-Chloro-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide 4-Ethyl-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide 4-Cyano-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethylsulfanyl-benzenesulfonamide 4-Trifluoromethyl-N-[2-(2-trifluoromethyl-pyrimidin-4-yl)-2H-pyrazol-3-yl]-benzenesulfonamide 2-Fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethanesulfonyl-benzenesulfonamide 3-Fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide N-[2-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-2H-pyrazol-3-yl]-4-ethyl-benzenesulfonamide and 4-Chloro-2-fluoro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide, or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, and a therapeutically inert carrier.

4. A compound selected from the group consisting of 4-Chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide 4-Ethyl-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide 4-Propyl-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide 2-Chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide 4-Difluoromethoxy-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide 4-Chloro-N-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-benzenesulfonamide 4-Cyano-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide N-[2-(4-Methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide 4-Chloro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide 4-Ethyl-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide N-(2-Pyrimidin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide 2,4-Dichloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide 4-Chloro-2-fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide 4-(1-Fluoro-ethyl)-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide N-[2-(4-Methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide 4-Chloro-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide 4-Ethyl-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide 4-Cyano-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethylsulfanyl-benzenesulfonamide 4-Trifluoromethyl-N-[2-(2-trifluoromethyl-pyrimidin-4-yl)-2H-pyrazol-3-yl]-benzenesulfonamide 2-Fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethanesulfonyl-benzenesulfonamide 3-Fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide N-[2-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-2H-pyrazol-3-yl]-4-ethyl-benzenesulfonamide and 4-Chloro-2-fluoro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.

5. A compound of formula IA, ##STR00035## wherein A.sup.1 is thiazolyl, pyrimidinyl or 1,2,4-thiadiazolyl; R.sup.1 is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen or cycloalkyl; A.sup.2 is phenyl; R.sup.2 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano, S-lower alkyl substituted by halogen, S(O).sub.2-lower alkyl substituted by halogen; n is 1 or 2; or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.

6. A compound selected from the group consisting of N-[2-(4-Methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide 4-Chloro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide 4-Ethyl-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide N-(2-Pyrimidin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide 4-Trifluoromethyl-N-[2-(2-trifluoromethyl-pyrimidin-4-yl)-2H-pyrazol-3-yl]-benzenesulfonamide N-[2-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-2H-pyrazol-3-yl]-4-ethyl-benzenesulfonamide and 4-Chloro-2-fluoro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide.

7. A process for preparation of a compound of formula IA, or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof, which process comprises a) reacting a compound of formula ##STR00036## with a compound of formula ##STR00037## to afford the compound of formula IA wherein formula IA is as follows ##STR00038## wherein A.sup.1 is thiazolyl, pyrimidinyl or 1,2,4-thiadiazolyl; R.sup.1 is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen or cycloalkyl; A.sup.2 is phenyl; R.sup.2 is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, cyano, S-lower alkyl substituted by halogen, S(O).sub.2-lower alkyl substituted by halogen; n is 1 or 2.

Description

EXPERIMENTAL PART

Example 1

4-Chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide

(1) ##STR00008##

(2) A mixture of 16.2 mg (0.1 mmol) 2-pyridin-2-yl-2H-pyrazol-3-ylamine (commercially available) and 26.4 mg (0.125 mmol) 4-chlorobenzene-1-sulfonyl chloride in 1 mL pyridine was reacted at room temperature overnight and evaporated. The residue was taken up in methanol and formic acid and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 20.7 mg (58%) of the title compound as viscous yellow oil. MS(m/e): 335.3 (MH.sup.+).

Example 2

N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide

(3) ##STR00009##

(4) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 2-pyridin-2-yl-2H-pyrazol-3-ylamine (commercially available) and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (commercially available) and isolated as off-white solid. MS(m/e): 369.1 (MH.sup.+).

Example 3

4-Ethyl-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide

(5) ##STR00010##

(6) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 2-pyridin-2-yl-2H-pyrazol-3-ylamine (commercially available) and 4-ethylbenzene-1-sulfonyl chloride (commercially available) and isolated as yellow viscous oil. MS(m/e): 329.4 (MH.sup.+).

Example 4

4-Propyl-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide

(7) ##STR00011##

(8) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 2-pyridin-2-yl-2H-pyrazol-3-ylamine (commercially available) and 4-propylbenzene-1-sulfonyl chloride (commercially available) and isolated as yellow viscous oil. MS(m/e): 343.4 (MH.sup.+).

Example 5

2-Chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide

(9) ##STR00012##

(10) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 2-pyridin-2-yl-2H-pyrazol-3-ylamine (commercially available) and 2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (commercially available) and isolated as light yellow solid. MS(m/e): 403.4 (MH.sup.+).

Example 6

4-Difluoromethoxy-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide

(11) ##STR00013##

(12) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 2-pyridin-2-yl-2H-pyrazol-3-ylamine (commercially available) and 4-(difluoromethoxy)benzene-1-sulfonyl chloride (commercially available) and isolated as yellow viscous oil. MS(m/e): 367.4 (MH.sup.+).

Example 7

4-Chloro-N-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-benzenesulfonamide

(13) ##STR00014##

(14) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 1-(4-fluorophenyl)-1H-pyrazol-5-amine (commercially available) and 4-chlorobenzene-1-sulfonyl chloride (commercially available). MS(m/e): 352.4 (MH.sup.+).

Example 8

4-Cyano-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide

(15) ##STR00015##

(16) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 2-pyridin-2-yl-2H-pyrazol-3-ylamine (commercially available) and 4-cyanobenzene-1-sulfonyl chloride (commercially available) and isolated as off-white solid. MS(m/e): 326.4 (MH.sup.+).

Example 9

N-[2-(4-Methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide

(17) ##STR00016##

a) 2-(4-Methyl-thiazol-2-yl)-2H-pyrazol-3-ylamine

(18) A mixture of 2-hydrazinyl-4-methylthiazole hydrochloride (5 g, 30.2 mmol) and DIPEA (7.8 g, 10.5 mL, 60.4 mmol) in N,N-dimethylacetamide (150 mL) was treated with of 3-(dimethylamino)acrylonitrile (2.9 g, 3.05 mL, 30.2 mmol) and heated to 145 C. for 4 h. The solution was cooled to room temperature and concentrated in high vacuo. The residue was dissolved in DCM (50 mL), absorbed on Isolute HM-N (30 g) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient formed from heptane and ethyl acetate to yield after evaporation of the product containing fractions 530 mg (9.5%) of the title compound as light brown solid. MS(m/e): 181.2 (MH.sup.+).

b) N-[2-(4-Methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide

(19) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-ylamine and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (commercially available) and isolated as light yellow solid. MS(m/e): 389.5 (MH.sup.+).

Example 10

4-Chloro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide

(20) ##STR00017##

(21) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-ylamine and 4-chlorobenzene-1-sulfonyl chloride (commercially available) and isolated as orange solid. MS(m/e): 355.4 (MH.sup.+).

Example 11

4-Ethyl-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide

(22) ##STR00018##

(23) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-ylamine and 4-ethylbenzene-1-sulfonyl chloride (commercially available) and isolated as orange solid. MS(m/e): 349.5 (MH.sup.+).

Example 12

N-(2-Pyrimidin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide

(24) ##STR00019##

(25) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 1-(pyrimidin-2-yl)-1H-pyrazol-5-amine (commercially available) and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (commercially available). MS(m/e): 370.5 (MH.sup.+).

Example 13

2,4-Dichloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide

(26) ##STR00020##

(27) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 2-pyridin-2-yl-2H-pyrazol-3-ylamine (commercially available) and 2,4-dichlorobenzene-1-sulfonyl chloride (commercially available). MS(m/e): 367.4 (MH.sup.+).

Example 14

4-Chloro-2-fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide

(28) ##STR00021##

(29) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 2-pyridin-2-yl-2H-pyrazol-3-ylamine (commercially available) and 4-chloro-2-fluorobenzene-1-sulfonyl chloride (commercially available). MS(m/e): 351.4 (MH.sup.+).

Example 15

4-(1-Fluoro-ethyl)-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide

(30) ##STR00022##

a) 4-Acetyl-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide

(31) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 2-pyridin-2-yl-2H-pyrazol-3-ylamine (commercially available) and 4-acetylbenzene-1-sulfonyl chloride (commercially available) and isolated as light brown solid. MS(m/e): 343.5 (MH.sup.+).

b) 4-(1-Hydroxy-ethyl)-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide

(32) A mixture of 4-acetyl-N-(1-(pyridin-2-yl)-1H-pyrazol-5-yl)benzenesulfonamide (200 mg, 0.584 mmol) and NaBH.sub.4 (22.1 mg, 0.584 mmol) in THF (20 mL)/MeOH (5 mL) was stirred overnight at room temperature. Na.sub.2CO.sub.3-solution (10%, aq.) was added and stirred for 30 min. The pH was adjusted to pH 6-7 and the mixture was extracted with ethyl acetate (230 mL). The organic layers were washed with brine (150 mL), dried over Na.sub.2SO.sub.4, filtered off and concentrated in vacuo to yield the title compound (193 mg, 0.56 mmol, 96%) as off-white waxy-solid. MS(m/e): 345.5 (MH.sup.+).

c) 4-(1-Fluoro-ethyl)-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide

(33) A mixture of 4-(1-hydroxyethyl)-N-(1-(pyridin-2-yl)-1H-pyrazol-5-yl)benzenesulfonamide (100 mg, 0.290 mmol) and DAST (51.5 mg, 42.2 l, 0.319 mmol) in DCM (11 mL) at 0-5 C. was stirred for 1 h. NaHCO.sub.3-solution (5%, aq., 5 mL) was added and the pH adjusted to pH 6-7. The organic layer was separated and the aqueous layer was extracted with DCM (25 mL). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered off and concentrated in vacuo. The residue was dissolved in methanol (4 mL) and subjected to purification by preparative HPLC on reversed phase to yield after evaporation of the product containing fractions 57 mg (55%) of the title compound as colorless viscous oil. MS(m/e): 347.6 (MH.sup.+).

Example 16

N-[2-(4-Methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-4-trifluoromethyl-benzenesulfonamide

(34) ##STR00023##

(35) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 1-(4-methylpyridin-2-yl)-1H-pyrazol-5-amine (commercially available) and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (commercially available). MS(m/e): 383.5 (MH.sup.+).

Example 17

4-Chloro-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide

(36) ##STR00024##

(37) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 1-(4-methylpyridin-2-yl)-1H-pyrazol-5-amine (commercially available) and 4-chlorobenzene-1-sulfonyl chloride (commercially available). MS(m/e): 349.5 (MH.sup.+).

Example 18

4-Ethyl-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide

(38) ##STR00025##

(39) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 1-(4-methylpyridin-2-yl)-1H-pyrazol-5-amine (commercially available) and 4-ethylbenzene-1-sulfonyl chloride (commercially available). MS(m/e): 343.6 (MH.sup.+).

Example 19

4-Cyano-N-[2-(4-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide

(40) ##STR00026##

(41) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 1-(4-methylpyridin-2-yl)-1H-pyrazol-5-amine (commercially available) and 4-cyanobenzene-1-sulfonyl chloride (commercially available). MS(m/e): 340.5 (MH.sup.+).

Example 20

N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethylsulfanyl-benzenesulfonamide

(42) ##STR00027##

(43) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 2-pyridin-2-yl-2H-pyrazol-3-ylamine (commercially available) and 4-(trifluoromethylthio)benzene-1-sulfonyl chloride (commercially available) and isolated as off-white solid. MS(m/e): 401.5 (MH.sup.+).

Example 21

4-Trifluoromethyl-N-[2-(2-trifluoromethyl-pyrimidin-4-yl)-2H-pyrazol-3-yl]-benzenesulfonamide

(44) ##STR00028##

a) 2-(2-Trifluoromethyl-pyrimidin-4-yl)-2H-pyrazol-3-ylamine

(45) A mixture of 4-hydrazinyl-2-(trifluoromethyl)pyrimidine (533 mg, 2.99 mmol) and (E)-3-(dimethylamino)acrylonitrile (288 mg, 2.99 mmol) were heated to 145 C. for 90 min. The mixture was cooled to room temperature, dissolved in DCM (5 mL) and absorbed on isolute HM-N. The mixture was concentrated in vacuo and purified by silica gel chromatography eluting with a gradient formed from heptane and ethyl acetate to yield after evaporation of the product containing fractions 500 mg (73%) of the title compound as yellow solid. MS(m/e): 230.2 (MH.sup.+).

b) 4-Trifluoromethyl-N-[2-(2-trifluoromethyl-pyrimidin-4-yl)-2H-pyrazol-3-yl]-benzenesulfonamide

(46) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 1-(2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-5-amine and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (commercially available). MS(m/e): 436.6 (MH.sup.+).

Example 22

2-Fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide

(47) ##STR00029##

(48) 2-Fluoro-4-trifluoromethyl-benzenesulfonyl chloride was synthesized in analogy to the flow procedure described in Preparation of arylsulfonyl chlorides by chlorosulfonylation of in situ generated diazonium salts using a continuous flow reactor by Malet-Sanz L., Madrzak J., Ley S. V., Baxendale I. R. in Org Biomol Chem 2010, 8, 5324-5332 from 2-fluoro-4-(trifluoromethyl)aniline (commercially available) and subsequently reacted in analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) with 1-(pyridin-2-yl)-1H-pyrazol-5-amine (commercially available) and isolated as brown solid. MS(m/e): 387.4 (MH.sup.+).

Example 23

N-(2-Pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethanesulfonyl-benzenesulfonamide

(49) ##STR00030##

(50) 4-Trifluoromethanesulfonyl-benzenesulfonyl chloride was synthesized in analogy to the flow procedure described in Preparation of arylsulfonyl chlorides by chlorosulfonylation of in situ generated diazonium salts using a continuous flow reactor by Malet-Sanz L., Madrzak J., Ley S. V., Baxendale I. R. in Org Biomol Chem 2010, 8, 5324-5332 from 4-(trifluoromethylsulfonyl)aniline (commercially available) and subsequently reacted in analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) with 1-(pyridin-2-yl)-1H-pyrazol-5-amine (commercially available) and isolated as light brown solid. MS(m/e): 433.5 (MH.sup.+).

Example 24

3-Fluoro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-4-trifluoromethyl-benzenesulfonamide

(51) ##STR00031##

(52) 3-Fluoro-4-trifluoromethyl-benzenesulfonyl chloride was synthesized in analogy to the flow procedure described in Preparation of arylsulfonyl chlorides by chlorosulfonylation of in situ generated diazonium salts using a continuous flow reactor by Malet-Sanz L., Madrzak J., Ley S. V., Baxendale I. R. in Org Biomol Chem 2010, 8, 5324-5332 from 3-fluoro-4-(trifluoromethyl)aniline (commercially available) and subsequently reacted in analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) with 1-(pyridin-2-yl)-1H-pyrazol-5-amine (commercially available) and isolated as light brown solid. MS(m/e): 387.5 (MH.sup.+).

Example 25

N-[2-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-2H-pyrazol-3-yl]-4-ethyl-benzenesulfonamide

(53) ##STR00032##

a) 2-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-2H-pyrazol-3-ylamine

(54) A mixture of 5-chloro-3-cyclopropyl-1,2,4-thiadiazole (1.22 g, 7.6 mmol) and hydrazine monohydrate (1.9 g, 1.85 ml, 38.0 mmol) in ethanol (50 mL) was heated for 1 h at reflux temperature. The mixture was cooled to room temperature, concentrated in vacuo and dried in high vacuo at 60 C. The residue was combined with 3-(dimethylamino)acrylonitrile (1.83 g, 1.92 ml, 19.0 mmol) and N,N-dimethylacetamide (30 mL) and heated for 2 h to 145 C. After 1 h a further portion of 3-(dimethylamino)acrylonitrile (1.1 g, 1.15 ml, 11.4 mmol) was added. The solution was cooled to room temperature and concentrated in high vacuo. The residue was dissolved in DCM (15 mL), absorbed on Isolute HM, concentrated in vacuo and purified by silica gel chromatography eluting with a gradient formed from heptane and ethyl acetate to yield after evaporation of the product containing fractions 940 mg (60%) of the title compounds as off-white solid. MS(m/e): 208.2 (MH.sup.+).

b) N-[2-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-2H-pyrazol-3-yl]-4-ethyl-benzenesulfonamide

(55) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 2-(3-cyclopropyl-[1,2,4]thiadiazol-5-yl)-2H-pyrazol-3-ylamine and 4-ethylbenzene-1-sulfonyl chloride (commercially available). MS(m/e): 374.5 (MH.sup.+).

Example 26

4-Chloro-2-fluoro-N-[2-(4-methyl-thiazol-2-yl)-2H-pyrazol-3-yl]-benzenesulfonamide

(56) ##STR00033##

(57) In analogy to the procedure described for the synthesis of 4-chloro-N-(2-pyridin-2-yl-2H-pyrazol-3-yl)-benzenesulfonamide (example 1) the title compound was prepared from 2-(4-Methyl-thiazol-2-yl)-2H-pyrazol-3-ylamine and 4-chloro-2-fluorobenzene-1-sulfonyl chloride (commercially available) and isolated as off white solid. MS(m/e): 373.5 (MH.sup.+).

(58) The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention have a good affinity to the oxytocin receptor. The compounds were investigated in accordance with the test given hereinafter.

(59) Material and Methods

(60) Cell Culture and Stable Clone Production

(61) Chinese Hamster Ovary (CHO) cells were transfected with expression plasmids encoding either the human V1a, the human Oxytocin (OTR) or the humanV2 receptor, the latter in combination with the chimeric Gqs5 G protein to redirect the signal to Calcium flux. Stable cells were cloned by limiting dilution to yield monoclonal cell lines expressing either human V1a, human V2+Gqs5 or human OTR receptors and selected based on functional responses detected on a fluorometric imaging plate reader (FLIPR) detecting Calcium flux in the cell after receptor activation. The stable cell lines were grown in F-12 K Nutrient Mixture (Kaighns Modification), containing 10% foetal bovine serum (FBS), 1% penicillin-streptomycin, 1% L-glutamate, 200 ug/ml Geneticin at 37 C. in a 10% CO.sub.2 incubator at 95% humidity.

(62) Calcium Flux Assays Using Fluorescent Imaging (Fluorometric Imaging Plate Reader, FLIPR)

(63) On the afternoon before the assay, cells were plated at a density of 50,000 cells/well into black 96 well plates with clear bottoms to allow cell inspection and fluorescence measurements from the bottom of each well. The density of cells was sufficient to yield a confluent monolayer the next day. Hanks balanced salt solution, without phenol red, containing 20 mM HEPES (pH 7.3) and 2.5 mM probenecid (assay buffer) was prepared fresh for each experiment. Compound dilutions were made using a Beckman Biomek 2000 laboratory automation workstation, in assay buffer containing 1% DMSO. The dye-loading buffer consisted of a final concentration of 2 M Fluo-4-AM (dissolved in DMSO and pluronic acid) in assay buffer. The existing culture media was removed from the wells and 100 l of the dye-loading buffer was added to each well and incubated for approximately 60 min at 37 C. in a 5% CO.sub.2 incubator at 95% humidity. Once dye-loaded, the cells were washed thoroughly on an Embla cell washer with the assay buffer to remove any unincorporated dye. Exactly 100 l assay buffer was left in each well.

(64) Each 96 well plate containing dye-loaded cells was placed into the FLIPR machine and the laser intensity set to a suitable level to detect low basal fluorescence. To test compounds as agonists, 25 l diluted compound was added to the plate 10 seconds into the fluorescent measurements and fluorescent response was recorded for 5 minutes. The fluorescence data was normalized to the endogenous full agonist dose-response set at 100% for the maximum response and 0% for the minimum. Each agonist concentration-response curve was constructed using a four parameter logistic equation with Microsoft Excel XLFit as follows: Y=Minimum+((MaximumMinimum)/(1+10.sup.(LogEC50-X)nH)), where y is the % normalized fluorescence, minimum is the minimum y, maximum is the maximum y, log EC.sub.50 is the log.sub.10 concentration which produces 50% of the maximum induced fluorescence, x is the log.sub.10 of the concentration of the agonist compound and H is the slope of the curve (the Hill Coefficient). The maximum value gives the efficacy of the agonist test compound in percentage. The concentration of agonist that produced a half-maximal response is represented by the EC.sub.50 value, the logarithm of which yielded the pEC.sub.50 value.

(65) The following hEC.sub.50 (uM) for the specific compounds may be provided in table 1:

(66) TABLE-US-00001 TABLE 1 hEC.sub.50 Example (uM) 1 0.019 2 0.008 3 0.016 4 0.034 5 0.091 6 0.107 7 2.46 8 0.081 9 0.52 10 0.163 11 0.113 12 1.8 13 0.017 14 0.019 15 0.084 16 0.017 17 0.016 18 0.02 19 0.063 20 0.047 21 1.57 22 0.333 23 0.753 24 0.799 25 1.57 26 0.15

(67) The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, drages, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

(68) The compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, drages and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

(69) The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

(70) Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

(71) The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.

(72) TABLE-US-00002 Tablet Formulation (Wet Granulation) mg/tablet Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167 831
Manufacturing Procedure 1. Mix items 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50 C. 3. Pass the granules through suitable milling equipment. 4. Add item 5 and mix for three minutes; compress on a suitable press.

(73) TABLE-US-00003 Capsule Formulation mg/capsule Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159 123 148 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 Total 200 200 300 600
Manufacturing Procedure 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add items 4 and 5 and mix for 3 minutes. 3. Fill into a suitable capsule.