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BUMETANIDE DERIVATIVES FOR THE THERAPY OF HYPERHIDROSIS

20210022978 ยท 2021-01-28

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to bumetanide derivatives of formula (I) as well as pharmaceutical compositions comprising these compounds for use in the treatment or prevention of diseases/disorders involving Na.sup.+K.sup.+2Cl.sup.-cotransporters (NKCCs), and particularly for use in the treatment or prevention of hyperhidrosis.

    ##STR00001##

    Claims

    1. A compound of formula (I) ##STR00259## wherein: the ring moiety is or ##STR00260## R.sup.x is R.sup.1 or R.sup.3; R.sup.1 is selected from COOH, COO(C.sub.1-15 alkyl), COO(C.sub.0-15 alkylene)-carbocyclyl, COO(C.sub.0-15 alkylene)-heterocyclyl, OCHO, OCO(C.sub.1-15 alkyl), OCO(C.sub.1-15 alkylene)-carbocyclyl, OCO(C.sub.0-15 alkylene)-heterocyclyl, CHO, CO(C.sub.1-15 alkyl), CO(C.sub.0-15 alkylene)-carbocyclyl, CO(C.sub.0-15 alkylene)-heterocyclyl, CONH.sub.2, CON(R.sup.11)(C.sub.1-15 alkyl), CON(R.sup.11)(C.sub.0-15 alkylene)-carbocyclyl, CON(R.sup.11)(C.sub.0-15 alkylene)-heterocyclyl, N(R.sup.11)CHO, N(R.sup.11)CO(C.sub.1-15 alkyl), N(R.sup.11)CO(C.sub.0-15 alkylene)-carbocyclyl, N(R.sup.11)CO(C.sub.0-15 alkylene)-heterocyclyl, C.sub.1-15 alkyl, (C.sub.0-15 alkylene)-carbocyclyl, (C.sub.0-15 alkylene)-heterocyclyl, C.sub.2-15 alkenyl, (C.sub.2-15 alkenylene)-carbocyclyl, (C.sub.2-15 alkenylene)-heterocyclyl, C.sub.2-15 alkynyl, (C.sub.2-15 alkynylene)-carbocyclyl and (C.sub.2-15 alkynylene)-heterocyclyl, wherein the alkyl moiety of any of the aforementioned groups, the alkylene moiety of any of the aforementioned groups, the alkenylene moiety of any of the aforementioned groups, the alkynylene moiety of any of the aforementioned groups, said C.sub.1-15 alkyl, said C.sub.2-15 alkenyl and said C.sub.2-15 alkynyl are each optionally substituted with one or more groups independently selected from halogen, CF.sub.3, CN, NO.sub.2, N(R.sup.11)(R.sup.11), O(R.sup.11), S(R.sup.11) and SO.sub.3H, wherein one or more CH.sub.2 units comprised in the alkyl moiety of any of the aforementioned groups, in the alkylene moiety of any of the aforementioned groups, in the alkenylene moiety of any of the aforementioned groups, in the alkynylene moiety of any of the aforementioned groups, in said C.sub.1-15 alkyl, in said C.sub.2-15 alkenyl, or in said C.sub.2-15 alkynyl are each optionally replaced by a group independently selected from O, CO, COO, OCO, N(R), N(R.sup.11)CO, CON(R.sup.11), S, SO, SO.sub.2, SO.sub.2N(R.sup.11) and N(R.sup.11)SO.sub.2, and further wherein the carbocyclyl moiety of any of the aforementioned groups and the heterocyclyl moiety of any of the aforementioned groups are each optionally substituted with one or more groups independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen, C.sub.1-6 haloalkyl, CN, NO.sub.2, N(R.sup.11)(R.sup.11), O(R.sup.1), S(R.sup.1), SO.sub.3H, carbocyclyl and heterocyclyl; each R.sup.11 is independently hydrogen or C.sub.1-6 alkyl; R.sup.2 is selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, OH, O(C.sub.1-6 alkyl), O(C.sub.1-6 alkylene)-OH, O(C.sub.1-6 alkylene)-O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, C.sub.1-6 haloalkyl, O(C.sub.1-6 haloalkyl), CN, NO.sub.2, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), OCO(C.sub.1-6 alkyl), CONH.sub.2, CONH(C.sub.1-6 alkyl), CON(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)-CO(C.sub.1-6 alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHSO.sub.2(C.sub.1-6 alkyl) and N(C.sub.1-6 alkyl)-SO.sub.2(C.sub.1-6 alkyl); R.sup.3 is selected from SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkylidene) and SO.sub.2-halogen, wherein the alkyl moiety of said SO.sub.2NH(C.sub.1-6 alkyl), one or both of the alkyl moieties of said SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), and the alkylidene moiety of said SO.sub.2N(C.sub.1-6 alkylidene) are each optionally substituted with one or more groups independently selected from halogen, CF.sub.3, CN, NO.sub.2, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), OH, O(C.sub.1-6 alkyl), SH and S(C.sub.1-6 alkyl); R.sup.4 is a group R.sup.4a, and R.sup.5 is a group R.sup.5a, or R.sup.4 and R.sup.5 are mutually linked to form a group R.sup.5b; R.sup.4a is selected from OR.sup.41, SR.sup.41, NHR.sup.41, N(C.sub.1-6 alkyl)-R.sup.41, halogen, hydrogen, carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R.sup.42; R.sup.41 is selected from (C.sub.0-4 alkylene)-carbocyclyl, (C.sub.0-4 alkylene)-heterocyclyl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl, wherein the carbocyclyl moiety of said (C.sub.0-4 alkylene)-carbocyclyl and the heterocyclyl moiety of said (C.sub.1-4 alkylene)-heterocyclyl are each optionally substituted with one or more groups R.sup.42, and wherein said C.sub.1-6 alkyl, said C.sub.2-6 alkenyl, said C.sub.2-6 alkynyl, the alkylene moiety of said (C.sub.0-4 alkylene)-carbocyclyl, and the alkylene moiety of said (C.sub.1-4 alkylene)-heterocyclyl are each optionally substituted with one or more groups R.sup.43; each R.sup.42 is independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, OH, O(C.sub.1-6 alkyl), O(C.sub.1-6 alkylene)-OH, O(C.sub.1-6 alkylene)-O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, C.sub.1-6 haloalkyl, O(C.sub.1-6 haloalkyl), CN, NO.sub.2, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), OCO(C.sub.1-6 alkyl), CONH.sub.2, CONH(C.sub.1-6 alkyl), CON(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)-CO(C.sub.1-6 alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHSO.sub.2(C.sub.1-6 alkyl) and N(C.sub.1-6 alkyl)-SO.sub.2(C.sub.1-6 alkyl); each R.sup.43 is independently selected from OH, O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, CF.sub.3, CN, NO.sub.2, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), OCO(C.sub.1-6 alkyl), CONH.sub.2, CONH(C.sub.1-6 alkyl), CON(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl) and N(C.sub.1-6 alkyl)-CO(C.sub.1-6 alkyl); R.sup.5a is selected from NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NO.sub.2 and hydrogen, wherein the alkyl moiety of said NH(C.sub.1-6 alkyl) and one or both of the alkyl moieties of said N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl) are each optionally substituted with one or more groups independently selected from halogen, CF.sub.3, CN, NO.sub.2, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), OH, O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R.sup.51; each R.sup.51 is independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, OH, O(C.sub.1-6 alkyl), O(C.sub.1-6 alkylene)-OH, O(C.sub.1-6 alkylene)-O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, C.sub.1-6 haloalkyl, O(C.sub.1-6 haloalkyl), CN, NO.sub.2, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), OCO(C.sub.1-6 alkyl), CONH.sub.2, CONH(C.sub.1-6 alkyl), CON(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)-CO(C.sub.1-6 alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHSO.sub.2(C.sub.1-6 alkyl) and N(C.sub.1-6 alkyl)-SO.sub.2(C.sub.1-6 alkyl); R.sup.5b is selected from R.sup.5b1R.sup.5b2R.sup.5b1, NC(R.sup.53)R.sup.5b3R.sup.5b1, R.sup.5b1R.sup.5b3C(R.sup.53)N, and NC(R.sup.53)R.sup.5b4C(R.sup.53)N; each R.sup.5b1 is independently selected from N(R.sup.52), O and S; R.sup.5b2 is selected from C(R.sup.53)(R.sup.53), C(R.sup.53)(R.sup.53)C(R.sup.53)(R.sup.53), C(R.sup.53)C(R.sup.53), C(R.sup.53)(R.sup.53)C(R.sup.53)C(R.sup.53) and C(R.sup.53)C(R.sup.53)C(R.sup.53)(R.sup.53); R.sup.5b3 is selected from a covalent bond, C(R.sup.53)(R.sup.53), C(R.sup.53)(R.sup.53)C(R.sup.53)(R.sup.53) and C(R.sup.53)C(R.sup.53); R.sup.5b4 is selected from a covalent bond and C(R.sup.53)(R.sup.53); each R.sup.52 is independently selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (C.sub.0-4 alkylene)-aryl and (C.sub.0-4 alkylene)-heteroaryl; each R.sup.53 is independently selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, OH, O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, C.sub.1-6 haloalkyl, O(C.sub.1-6 haloalkyl), CN, NO.sub.2, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), OCO(C.sub.1-6 alkyl), CONH.sub.2, CONH(C.sub.1-6 alkyl), CON(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)-CO(C.sub.1-6 alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHSO.sub.2(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)-SO.sub.2(C.sub.1-6 alkyl), (C.sub.0-4 alkylene)-aryl and (C.sub.0-4 alkylene)-heteroaryl, and any two groups R.sup.53 that are attached to the same carbon atom may also together form a group O, and any two groups R.sup.53 that are attached to adjacent carbon atoms connected by a double bond may also be mutually linked to form a group C(R.sup.54)C(R.sup.54)C(R.sup.5)C(R.sup.54); each R.sup.54 is independently selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, OH, O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, C.sub.1-6 haloalkyl, O(C.sub.1-6 haloalkyl), CN, NO.sub.2, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), OCO(C.sub.1-6 alkyl), CONH.sub.2, CONH(C.sub.1-6 alkyl), CON(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)-CO(C.sub.1-6 alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHSO.sub.2(C.sub.1-6 alkyl) and N(C.sub.1-6 alkyl)-SO.sub.2(C.sub.1-6 alkyl); and R.sup.6 is selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, OH, O(C.sub.1-6 alkyl), O(C.sub.1-6 alkylene)-OH, O(C.sub.1-6 alkylene)-O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, C.sub.1-6 haloalkyl, O(C.sub.1-6 haloalkyl), CN, NO.sub.2, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), OCO(C.sub.1-6 alkyl), CONH.sub.2, CONH(C.sub.1-6 alkyl), CON(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)-CO(C.sub.1-6 alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHSO.sub.2(C.sub.1-6 alkyl) and N(C.sub.1-6 alkyl)-SO.sub.2(C.sub.1-6alkyl); or R.sup.1 and R.sup.6 are mutually linked to form a group R.sup.16, wherein: R.sup.16 is a group C(R.sup.161)(R.sup.161)C(R.sup.161)(R.sup.161)C(R.sup.161)(R.sup.161)C(R.sup.161)(R.sup.161), wherein one or two C(R.sup.161)(R.sup.161) units comprised in said group are each replaced by R.sup.163; each R.sup.161 is independently selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen, C.sub.1-6 haloalkyl, (C.sub.0-6 alkylene)-CF.sub.3, (C.sub.0-6 alkylene)-CN, (C.sub.0-6 alkylene)-NO.sub.2, (C.sub.0-6 alkylene)-N(R.sup.162)(R.sup.162), (C.sub.0-6 alkylene)-O(R.sup.162), (C.sub.0-6 alkylene)-S(R.sup.162), (C.sub.0-6 alkylene)-SO.sub.3H, (C.sub.0-6 alkylene)-carbocyclyl and (C.sub.0-6 alkylene)-heterocyclyl; each R.sup.162 is independently hydrogen or C.sub.1-6 alkyl; and each R.sup.163 is independently selected from N(R.sup.161), O and S; with the proviso that, if the ring moiety ##STR00261## R.sup.2 is hydrogen, R.sup.3 is SO.sub.2NH.sub.2, R.sup.4 is O-phenyl, R.sup.5 is NHCH.sub.2CH.sub.2CH.sub.2CH.sub.3 and R.sup.6 is hydrogen, then R.sup.1 is different from COOH; or a pharmaceutically acceptable salt or solvate thereof for use in the treatment or prevention of hyperhidrosis.

    2. The compound for use according to claim 1, wherein the compound of formula (I) is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof: ##STR00262## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined in claim 1.

    3. The compound for use according to claim 2, wherein R.sup.1 is COO(C.sub.1-5 alkyl), wherein the alkyl moiety of said COO(C.sub.1-15 alkyl) is optionally substituted with one or more groups independently selected from halogen, CF.sub.3, CN, NO.sub.2, NH.sub.2, NH(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), OH, O(C.sub.1-4 alkyl), SH and S(C.sub.1-4 alkyl), and further wherein one or two CH.sub.2 units comprised in the alkyl moiety of said COO(C.sub.1-15 alkyl) are each optionally replaced by a group independently selected from O, CO, COO, OCO, NH, N(C.sub.1-4 alkyl)-, NHCO, N(C.sub.1-4 alkyl)-CO, CONH, CON(C.sub.1-4 alkyl)-, S, SO, SO.sub.2, SO.sub.2NH, SO.sub.2N(C.sub.1-4 alkyl)-, NHSO.sub.2 and N(C.sub.1-4 alkyl)-SO.sub.2.

    4. The compound for use according to claim 2 or 3, wherein R.sup.1 is COOCH.sub.3.

    5. The compound for use according to claim 2, wherein R.sup.1 is COOH.

    6. The compound for use according to claim 2, wherein R.sup.1 is selected from (C.sub.1-4 alkylene)-NH(C.sub.1-4 alkylene)-R.sup.12, COO(C.sub.1-4 alkylene)-R.sup.12, OCO(C.sub.1-4 alkylene)-R.sup.12, CO(C.sub.1-4 alkylene)-R.sup.12, CONH(C.sub.1-4 alkylene)-R.sup.12, CON(C.sub.1-4 alkyl)-(C.sub.1-4 alkylene)-R.sup.12, NHCO(C.sub.1-4 alkylene)-R.sup.12 and N(C.sub.1-4 alkyl)-CO(C.sub.1-4 alkylene)-R.sup.12, wherein R.sup.12 is independently selected from CF.sub.3, CN and halogen.

    7. The compound for use according to claim 2 or 6, wherein R.sup.1 is (C.sub.1-4 alkylene)-NH(C.sub.1-4 alkylene)-CF.sub.3.

    8. The compound for use according to any one of claims 2 to 7, wherein R.sup.2 is hydrogen.

    9. The compound for use according to any one of claims 2 to 8, wherein R.sup.3 is selected from SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-4 alkyl), SO.sub.2N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), and SO.sub.2N(C.sub.1-4 alkylidene), and further wherein the alkyl moiety of said SO.sub.2NH(C.sub.1-4 alkyl), one or both of the alkyl moieties of said SO.sub.2N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), and the alkylidene moiety of said SO.sub.2N(C.sub.1-4 alkylidene) are each optionally substituted with one group selected from NH.sub.2, NH(C.sub.1-4 alkyl) and N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl).

    10. The compound for use according to any one of claims 2 to 9, wherein R.sup.4 is a group R.sup.4a which is selected from O-aryl, O-heteroaryl, S-aryl, S-heteroaryl, NH-aryl, NH heteroaryl, N(C.sub.1-4 alkyl)-aryl, N(C.sub.1-4 alkyl)-heteroaryl, aryl and heteroaryl, and wherein the aryl moiety of any of the aforementioned groups, the heteroaryl moiety of any of the aforementioned groups, said aryl and said heteroaryl are each optionally substituted with one or more groups independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, OH, O(C.sub.1-6 alkyl), O(C.sub.1-6 alkylene)-OH, O(C.sub.1-6 alkylene)-O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, C.sub.1-6 haloalkyl and CN.

    11. The compound for use according to any one of claims 2 to 10, wherein R.sup.5 is a group R.sup.5a which is selected from NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), and NO.sub.2.

    12. The compound for use according to any one of claims 2 to 11, wherein R.sup.6 is hydrogen.

    13. The compound for use according to claim 1, wherein the compound of formula (I) is a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof: ##STR00263## wherein R.sup.x, R.sup.4, R.sup.5 and R.sup.6 are as defined in claim 1.

    14. The compound for use according to claim 13, wherein R is selected from COOH, COO(C.sub.1-6 alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-4 alkyl), SO.sub.2N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), and SO.sub.2N(C.sub.1-4 alkylidene), and further wherein the alkyl moiety of said SO.sub.2NH(C.sub.1-4 alkyl), one or both of the alkyl moieties of said SO.sub.2N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), and the alkylidene moiety of said SO.sub.2N(C.sub.1-4 alkylidene) are each optionally substituted with one group selected from NH.sub.2, NH(C.sub.1-4 alkyl) and N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl).

    15. The compound for use according to claim 13 or 14, wherein R.sup.4 is a group R.sup.4a which is O-aryl or halogen, and wherein the aryl moiety of said O-aryl is optionally substituted with one or more groups independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, OH, O(C.sub.1-6 alkyl), O(C.sub.1-6 alkylene)-OH, O(C.sub.1-6 alkylene)-O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, C.sub.1-6 haloalkyl and CN.

    16. The compound for use according to any one of claims 13 to 15, wherein R.sup.5 is a group R.sup.5a which is selected from NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), and NO.sub.2.

    17. The compound for use according to any one of claims 13 to 16, wherein R.sup.6 is hydrogen.

    18. The compound for use according to claim 1, wherein the compound of formula (I) is a compound of any one of the following formulae, or a pharmaceutically acceptable salt or solvate thereof: ##STR00264## ##STR00265## ##STR00266## ##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271## ##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276## ##STR00277## ##STR00278## ##STR00279## ##STR00280## ##STR00281## ##STR00282## ##STR00283## ##STR00284## ##STR00285## ##STR00286## ##STR00287## ##STR00288## ##STR00289## ##STR00290## Error! Objects cannot be created from editing field codes.Error! Objects cannot be created from editing field codes.Error! Objects cannot be created from editing field codes.

    19. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 18 and a pharmaceutically acceptable excipient for use in the treatment or prevention of hyperhidrosis.

    20. Use of a compound as defined in any one of claims 1 to 18 in the preparation of a medicament for the treatment or prevention of hyperhidrosis.

    21. A method of treating or preventing hyperhidrosis, the method comprising administering a compound as defined in any one of claims 1 to 18 or a pharmaceutical composition as defined in claim 19 to a subject in need thereof.

    22. The method of claim 21, wherein the subject is a human.

    23. Non-therapeutic use of a compound as defined in any one of claims 1 to 18 for suppressing or reducing the sweating of a subject.

    24. Non-therapeutic method of suppressing or reducing the sweating of a subject, wherein the method comprises administering a compound as defined in any one of claims 1 to 18 to the subject.

    25. The non-therapeutic use of claim 23 or the non-therapeutic method of claim 24, wherein said compound is administered topically.

    26. The non-therapeutic use of claim 23 or 25 or the non-therapeutic method of claim 24 or 25, wherein said compound is provided in the form of an article comprising said compound, wherein the article is a wipe, an insole or a garment.

    27. An article comprising a compound as defined in any one of claims 1 to 18, wherein the article is a wipe, an insole or a garment.

    28. A compound as defined in any one of claims 1 to 18 for use in the treatment or prevention of a disease or disorder selected from an anxiety disorder, an autism spectrum disorder, autism, Asperger syndrome, childhood disintegrative disorder, a pervasive developmental disorder as part of an autism spectrum disorder, traumatic brain injury, spinal cord injury, peripheral nerve injury, stroke, Alzheimer's disease, schizophrenia, asthma, edema, Down syndrome, mental disability in patients with Down syndrome, glaucoma, primary open angle glaucoma, angle closure glaucoma, and a parasitic infection, wherein said parasitic infection is preferably selected from a helminth infection, a hookworm infection, a roundworm infection, a whipworm infection, a tapeworm infection, a guinea worm infection, a pinworm infection, a toxocara infection, a Strongyloides stercoralis infection, an Ascaris lumbricoides infection, a parasitic fluke infection, Schistosomiasis, Gnathostomiasis, Paragonimiasis, Fascioliasis, Swimmer's itch, a protozoan infection, malaria, amoebiasis, giardiasis, African sleeping sickness, toxoplasmosis, Acanthamoeba keratitis, leishmaniasis, babesiosis, granulomatous amoebic encephalitis, cryptosporidiosis, cyclosporiasis, primary amoebic meningoencephalitis, an ectoparasitic infection, an infection with Sarcoptes scabiei, an infection with Pediculus humanus capitis, an infection with Phthirus pubis, an infection with human botfly maggots, an infection with Tunga penetrans, and an infection with Ixodoidea.

    29. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 18 and a pharmaceutically acceptable excipient for use in the treatment or prevention of a disease or disorder selected from an anxiety disorder, an autism spectrum disorder, autism, Asperger syndrome, childhood disintegrative disorder, a pervasive developmental disorder as part of an autism spectrum disorder, traumatic brain injury, spinal cord injury, peripheral nerve injury, stroke, Alzheimer's disease, schizophrenia, asthma, edema, Down syndrome, mental disability in patients with Down syndrome, glaucoma, primary open angle glaucoma, angle closure glaucoma, and a parasitic infection, wherein said parasitic infection is preferably selected from a helminth infection, a hookworm infection, a roundworm infection, a whipworm infection, a tapeworm infection, a guinea worm infection, a pinworm infection, a toxocara infection, a Strongyloides stercoralis infection, an Ascaris lumbricoides infection, a parasitic fluke infection, Schistosomiasis, Gnathostomiasis, Paragonimiasis, Fascioliasis, Swimmer's itch, a protozoan infection, malaria, amoebiasis, giardiasis, African sleeping sickness, toxoplasmosis, Acanthamoeba keratitis, leishmaniasis, babesiosis, granulomatous amoebic encephalitis, cryptosporidiosis, cyclosporiasis, primary amoebic meningoencephalitis, an ectoparasitic infection, an infection with Sarcoptes scabiei, an infection with Pediculus humanus capitis, an infection with Phthirus pubis, an infection with human botfly maggots, an infection with Tunga penetrans, and an infection with Ixodoidea.

    30. Use of a compound as defined in any one of claims 1 to 18 in the preparation of a medicament for the treatment or prevention of a disease or disorder selected from an anxiety disorder, an autism spectrum disorder, autism, Asperger syndrome, childhood disintegrative disorder, a pervasive developmental disorder as part of an autism spectrum disorder, traumatic brain injury, spinal cord injury, peripheral nerve injury, stroke, Alzheimer's disease, schizophrenia, asthma, edema, Down syndrome, mental disability in patients with Down syndrome, glaucoma, primary open angle glaucoma, angle closure glaucoma, and a parasitic infection, wherein said parasitic infection is preferably selected from a helminth infection, a hookworm infection, a roundworm infection, a whipworm infection, a tapeworm infection, a guinea worm infection, a pinworm infection, a toxocara infection, a Strongyloides stercoralis infection, an Ascaris lumbricoides infection, a parasitic fluke infection, Schistosomiasis, Gnathostomiasis, Paragonimiasis, Fascioliasis, Swimmer's itch, a protozoan infection, malaria, amoebiasis, giardiasis, African sleeping sickness, toxoplasmosis, Acanthamoeba keratitis, leishmaniasis, babesiosis, granulomatous amoebic encephalitis, cryptosporidiosis, cyclosporiasis, primary amoebic meningoencephalitis, an ectoparasitic infection, an infection with Sarcoptes scabiei, an infection with Pediculus humanus capitis, an infection with Phthirus pubis, an infection with human botfly maggots, an infection with Tunga penetrans, and an infection with Ixodoidea.

    31. A method of treating or preventing a disease/disorder, the method comprising administering a compound as defined in any one of claims 1 to 18 or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient to a subject in need thereof, wherein said disease/disorder selected from the group consisting of an anxiety disorder, an autism spectrum disorder, autism, Asperger syndrome, childhood disintegrative disorder, a pervasive developmental disorder as part of an autism spectrum disorder, traumatic brain injury, spinal cord injury, peripheral nerve injury, stroke, Alzheimer's disease, schizophrenia, asthma, edema, Down syndrome, mental disability in patients with Down syndrome, glaucoma, primary open angle glaucoma, angle closure glaucoma, and a parasitic infection, wherein said parasitic infection is preferably selected from the group consisting of a helminth infection, a hookworm infection, a roundworm infection, a whipworm infection, a tapeworm infection, a guinea worm infection, a pinworm infection, a toxocara infection, a Strongyloides stercoralis infection, an Ascaris lumbricoides infection, a parasitic fluke infection, Schistosomiasis, Gnathostomiasis, Paragonimiasis, Fascioliasis, Swimmer's itch, a protozoan infection, malaria, amoebiasis, giardiasis, African sleeping sickness, toxoplasmosis, Acanthamoeba keratitis, leishmaniasis, babesiosis, granulomatous amoebic encephalitis, cryptosporidiosis, cyclosporiasis, primary amoebic meningoencephalitis, an ectoparasitic infection, an infection with Sarcoptes scabiei, an infection with Pediculus humanus capitis, an infection with Phthirus pubis, an infection with human botfly maggots, an infection with Tunga penetrans, and an infection with lxodoidea.

    32. The method of claim 31, wherein the subject is a human.

    33. In vitro use of a compound as defined in any one of claims 1 to 18 as an NKCC inhibitor.

    34. An in vitro method of inhibiting NKCC, the method comprising the application of a compound as defined in any one of claims 1 to 18.

    35. A compound of any one of the following formulae or a pharmaceutically acceptable salt or solvate thereof: ##STR00291## ##STR00292## ##STR00293## ##STR00294## ##STR00295## ##STR00296## ##STR00297## ##STR00298## ##STR00299## ##STR00300## ##STR00301## ##STR00302## ##STR00303## ##STR00304## ##STR00305## ##STR00306## ##STR00307## ##STR00308## ##STR00309## ##STR00310## ##STR00311## ##STR00312## Error! Objects cannot be created from editing field codes.Error! Objects cannot be created from editing field codes.Error! Objects cannot be created from editing field codes.

    36. A compound as defined in claim 35 for use as a medicament.

    37. A pharmaceutical composition comprising a compound as defined in claim 35 and a pharmaceutically acceptable excipient.

    38. A compound of formula (Ia) ##STR00313## wherein: R.sup.1 is selected from COOH, COO(C.sub.1-15 alkyl), COO(C.sub.0-15 alkylene)-carbocyclyl, COO(C.sub.0-15 alkylene)-heterocyclyl, OCHO, OCO(C.sub.1-15 alkyl), OCO(C.sub.0-15 alkylene)-carbocyclyl, OCO(C.sub.0-15 alkylene)-heterocyclyl, CHO, CO(C.sub.1-15 alkyl), CO(C.sub.0-5 alkylene)-carbocyclyl, CO(C.sub.0-15 alkylene)-heterocyclyl, CONH.sub.2, CON(R.sup.11)(C.sub.1-15 alkyl), CON(R.sup.11)(C.sub.0-15 alkylene)-carbocyclyl, CON(R.sup.11)(C.sub.0-15 alkylene)-heterocyclyl, N(R.sup.11)CHO, N(R.sup.11)CO(C.sub.1-15 alkyl), N(R.sup.11)CO(C.sub.0-15 alkylene)-carbocyclyl, N(R.sup.11)CO(C.sub.0-15 alkylene)-heterocyclyl, C.sub.1-15 alkyl, (C.sub.0-15 alkylene)-carbocyclyl, (C.sub.0-15 alkylene)-heterocyclyl, C.sub.2-15 alkenyl, (C.sub.2-15 alkenylene)-carbocyclyl, (C.sub.2-15 alkenylene)-heterocyclyl, C.sub.2-15 alkynyl, (C.sub.2-15 alkynylene)-carbocyclyl and (C.sub.2-15 alkynylene)-heterocyclyl, wherein the alkyl moiety of any of the aforementioned groups, the alkylene moiety of any of the aforementioned groups, the alkenylene moiety of any of the aforementioned groups, the alkynylene moiety of any of the aforementioned groups, said C.sub.1-15 alkyl, said C.sub.2-15 alkenyl and said C.sub.2-15 alkynyl are each optionally substituted with one or more groups independently selected from halogen, CF.sub.3, CN, NO.sub.2, N(R.sup.11)(R.sup.11), O(R.sup.11), S(R.sup.11) and SO.sub.3H, wherein one or more CH.sub.2 units comprised in the alkyl moiety of any of the aforementioned groups, in the alkylene moiety of any of the aforementioned groups, in the alkenylene moiety of any of the aforementioned groups, in the alkynylene moiety of any of the aforementioned groups, in said C.sub.1-15 alkyl, in said C.sub.2-15 alkenyl, or in said C.sub.2-15 alkynyl are each optionally replaced by a group independently selected from O, CO, COO, OCO, N(R.sup.11), N(R.sup.11)CO, CON(R.sup.11), S, SO, SO.sub.2, SO.sub.2N(R.sup.11) and N(R.sup.11)SO.sub.2, and further wherein the carbocyclyl moiety of any of the aforementioned groups and the heterocyclyl moiety of any of the aforementioned groups are each optionally substituted with one or more groups independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen, C.sub.1-6 haloalkyl, CN, NO.sub.2, N(R.sup.11)(R.sup.11), O(R.sup.11), S(R.sup.11), SO.sub.3H, carbocyclyl and heterocyclyl; each R.sup.11 is independently hydrogen or C.sub.1-6 alkyl; R.sup.2 is selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, OH, O(C.sub.1-6 alkyl), O(C.sub.1-6 alkylene)-OH, O(C.sub.1-6 alkylene)-O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, C.sub.1-6 haloalkyl, O(C.sub.1-6 haloalkyl), CN, NO.sub.2, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), OCO(C.sub.1-6 alkyl), CONH.sub.2, CONH(C.sub.1-6 alkyl), CON(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)-CO(C.sub.1-6 alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHSO.sub.2(C.sub.1-6 alkyl) and N(C.sub.1-6 alkyl)-SO.sub.2(C.sub.1-6 alkyl); R.sup.3 is selected from SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkylidene) and SO.sub.2-halogen, wherein the alkyl moiety of said SO.sub.2NH(C.sub.1-6 alkyl), one or both of the alkyl moieties of said SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), and the alkylidene moiety of said SO.sub.2N(C.sub.1-6 alkylidene) are each optionally substituted with one or more groups independently selected from halogen, CF.sub.3, CN, NO.sub.2, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), OH, O(C.sub.1-6 alkyl), SH and S(C.sub.1-6 alkyl); R.sup.4 and R.sup.5 are mutually linked to form a group R.sup.5b; R.sup.5b is selected from R.sup.5b1R.sup.5b2R.sup.5b1, NC(R.sup.53)R.sup.5b3R.sup.5b1, R.sup.5b1R.sup.5b3C(R.sup.53)N, and NC(R.sup.53)R.sup.5b4C(R.sup.53)N; each R.sup.5b1 is independently selected from N(R.sup.52), O and S; R.sup.5b2 is selected from C(R.sup.53)(R.sup.53), C(R.sup.53)(R.sup.53)C(R.sup.53)(R.sup.53), C(R.sup.53)C(R.sup.53), C(R.sup.53)(R.sup.53)C(R.sup.53)C(R.sup.53) and C(R.sup.53)C(R.sup.53)C(R.sup.53)(R.sup.53); R.sup.5b3 is selected from a covalent bond, C(R.sup.53)(R.sup.53), C(R.sup.53)(R.sup.53)C(R.sup.53)(R.sup.53) and C(R.sup.53)C(R.sup.53); R.sup.5b4 is selected from a covalent bond and C(R.sup.53)(R.sup.53); each R.sup.52 is independently selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, (C.sub.0-4 alkylene)-aryl and (C.sub.0-4 alkylene)-heteroaryl; each R.sup.53 is independently selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, OH, O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, C.sub.1-6 haloalkyl, O(C.sub.1-6 haloalkyl), CN, NO.sub.2, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), OCO(C.sub.1-6 alkyl), CONH.sub.2, CONH(C.sub.1-6 alkyl), CON(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)-CO(C.sub.1-6 alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHSO.sub.2(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)-SO.sub.2(C.sub.1-6 alkyl), (C.sub.0-4 alkylene)-aryl and (C.sub.0-4 alkylene)-heteroaryl, and any two groups R.sup.53 that are attached to the same carbon atom may also together form a group O, and any two groups R.sup.53 that are attached to adjacent carbon atoms connected by a double bond may also be mutually linked to form a group C(R.sup.54)C(R.sup.54)C(R.sup.54)C(R.sup.54); each R.sup.54 is independently selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, OH, O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, C.sub.1-6 haloalkyl, O(C.sub.1-6 haloalkyl), CN, NO.sub.2, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), OCO(C.sub.1-6 alkyl), CONH.sub.2, CONH(C.sub.1-6 alkyl), CON(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)-CO(C.sub.1-6 alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHSO.sub.2(C.sub.1-6 alkyl) and N(C.sub.1-6 alkyl)-SO.sub.2(C.sub.1-6 alkyl); and R.sup.6 is selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, OH, O(C.sub.1-6 alkyl), O(C.sub.1-6 alkylene)-OH, O(C.sub.1-6 alkylene)-O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, C.sub.1-6 haloalkyl, O(C.sub.1-6 haloalkyl), CN, NO.sub.2, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), OCO(C.sub.1-6 alkyl), CONH.sub.2, CONH(C.sub.1-6 alkyl), CON(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)-CO(C.sub.1-6 alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHSO.sub.2(C.sub.1-6 alkyl) and N(C.sub.1-6 alkyl)-SO.sub.2(C.sub.1-6alkyl); or a pharmaceutically acceptable salt or solvate thereof.

    39. A compound as defined in claim 38 for use as a medicament.

    40. A pharmaceutical composition comprising a compound as defined in claim 38 and a pharmaceutically acceptable excipient.

    41. A compound of formula (Ib) ##STR00314## wherein: R.sup.x is selected from COOH, COO(C.sub.1-6 alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-4 alkyl), SO.sub.2N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), and SO.sub.2N(C.sub.1-4 alkylidene), wherein the alkyl moiety of said SO.sub.2NH(C.sub.1-4 alkyl), one or both of the alkyl moieties of said SO.sub.2N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl), and the alkylidene moiety of said SO.sub.2N(C.sub.1-4 alkylidene) are each optionally substituted with one group selected from NH.sub.2, NH(C.sub.1-4 alkyl) and N(C.sub.1-4 alkyl)(C.sub.1-4 alkyl); R.sup.4 is a group R.sup.4a, and R.sup.5 is a group R.sup.5a; R.sup.4a is selected from OR.sup.41, SR.sup.41, NHR.sup.41, N(C.sub.1-6 alkyl)-R.sup.41, halogen, carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R.sup.42; R.sup.41 is selected from (C.sub.0-4 alkylene)-carbocyclyl, (C.sub.0-4 alkylene)-heterocyclyl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl, wherein the carbocyclyl moiety of said (C.sub.0-4 alkylene)-carbocyclyl and the heterocyclyl moiety of said (C.sub.1-4 alkylene)-heterocyclyl are each optionally substituted with one or more groups R.sup.42, and wherein said C.sub.1-6 alkyl, said C.sub.2-6 alkenyl, said C.sub.2-6 alkynyl, the alkylene moiety of said (C.sub.0-4 alkylene)-carbocyclyl, and the alkylene moiety of said (C.sub.1-4 alkylene)-heterocyclyl are each optionally substituted with one or more groups R.sup.43; each R.sup.42 is independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, OH, O(C.sub.1-6 alkyl), O(C.sub.1-6 alkylene)-OH, O(C.sub.1-6 alkylene)-O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, C.sub.1-6 haloalkyl, O(C.sub.1-6 haloalkyl), CN, NO.sub.2, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), OCO(C.sub.1-6 alkyl), CONH.sub.2, CONH(C.sub.1-6 alkyl), CON(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)-CO(C.sub.1-6 alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHSO.sub.2(C.sub.1-6 alkyl) and N(C.sub.1-6 alkyl)-SO.sub.2(C.sub.1-6 alkyl); each R.sup.43 is independently selected from OH, O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, CF.sub.3, CN, NO.sub.2, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), OCO(C.sub.1-6 alkyl), CONH.sub.2, CONH(C.sub.1-6 alkyl), CON(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl) and N(C.sub.1-6 alkyl)-CO(C.sub.1-6 alkyl); R.sup.5a is selected from NH.sub.2, NH(C.sub.1-6 alkyl) and N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), wherein the alkyl moiety of said NH(C.sub.1-6 alkyl) and one or both of the alkyl moieties of said N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl) are each optionally substituted with one or more groups independently selected from halogen, CF.sub.3, CN, NO.sub.2, NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), OH, O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), carbocyclyl and heterocyclyl, wherein said carbocyclyl and said heterocyclyl are each optionally substituted with one or more groups R.sup.51; each R.sup.51 is independently selected from C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, OH, O(C.sub.1-6 alkyl), O(C.sub.1-6 alkylene)-OH, O(C.sub.1-6 alkylene)-O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, C.sub.1-6 haloalkyl, O(C.sub.1-6 haloalkyl), CN, NO.sub.2, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), OCO(C.sub.1-6 alkyl), CONH.sub.2, CONH(C.sub.1-6 alkyl), CON(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)-CO(C.sub.1-6 alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHSO.sub.2(C.sub.1-6 alkyl) and N(C.sub.1-6 alkyl)-SO.sub.2(C.sub.1-6 alkyl); and R.sup.6 is selected from hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, OH, O(C.sub.1-6 alkyl), O(C.sub.1-6 alkylene)-OH, O(C.sub.1-6 alkylene)-O(C.sub.1-6 alkyl), SH, S(C.sub.1-6 alkyl), NH.sub.2, NH(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), halogen, C.sub.1-6 haloalkyl, O(C.sub.1-6 haloalkyl), CN, NO.sub.2, CHO, CO(C.sub.1-6 alkyl), COOH, COO(C.sub.1-6 alkyl), OCO(C.sub.1-6 alkyl), CONH.sub.2, CONH(C.sub.1-6 alkyl), CON(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHCO(C.sub.1-6 alkyl), N(C.sub.1-6 alkyl)-CO(C.sub.1-6 alkyl), SO.sub.2NH.sub.2, SO.sub.2NH(C.sub.1-6 alkyl), SO.sub.2N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl), NHSO.sub.2(C.sub.1-6 alkyl) and N(C.sub.1-6 alkyl)-SO.sub.2(C.sub.1-6alkyl); or a pharmaceutically acceptable salt or solvate thereof.

    42. A compound as defined in claim 41 for use as a medicament.

    43. A pharmaceutical composition comprising a compound as defined in claim 41 and a pharmaceutically acceptable excipient.

    Description

    EXAMPLES

    [0386] The compounds described in this section are defined by their chemical formulae and their corresponding chemical names. In case of conflict between any chemical formula and the corresponding chemical name indicated herein, the present invention relates to both the compound defined by the chemical formula and the compound defined by the chemical name, and particularly relates to the compound defined by the chemical formula.

    Example 1: Synthesis of Various Compounds According to the Invention

    [0387] General Methods

    [0388] All chemicals and solvents were purchased from commercial suppliers (Sigma Aldrich, Merck, Apollo Scientific and TCI Europe) at analytical grade. Bumetanide was obtained from OChem Inc., Des Plaines, Ill., US.

    [0389] To monitor reactions via thin layer chromatography, silica gel F.sub.254 coated aluminum sheets from Merck were used.

    [0390] As a stationary phase for column chromatography silica gel 60 70-230 mesh ASTM from Merck was used.

    [0391] Melting points were measured on a ThermoGalen Kofler hot stage microscope.

    [0392] .sup.1H- and .sup.13C-NMR spectra were recorded on a Bruker Advance (200 and 50 MHz respectively) and chemical shifts are reported in ppm relatively to the solvent residual line or tetramethylsilane as internal standard.

    [0393] Mass spectra were recorded on a Shimadzu (GC-17A; MS-QP5050A) spectrometer. The peak intensity is specified in percent relative to the biggest signal in the spectrum.

    [0394] Elemental analysis were performed by Mag. Johannes Theiner at the University of Vienna and all reported values are within +/0.4% of the calculated values.

    Ethyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate (TEPS 1)

    [0395] ##STR00156##

    [0396] To a suspension of 5 mmol (1.82 g) bumetanide in 3 mL EtOH, 11 mmol (0.8 mL) SOC12 were added under argon atmosphere and stirred overnight. After completed conversion (monitored by TLC T/EtOAc 6+4) the mixture was extracted with 5% NaHCO.sub.3, saturated brine, and water several times. Then the organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The raw product was recrystallized from ethanol to yield 1.67 g (85%) TEPS 1. .sup.1H NMR (200 MHz, chloroform-d) 8.05-7.92 (m, 1H), 7.66-7.54 (m, 1H), 7.45-7.25 (m, 2H), 7.21-7.05 (m, 1H), 7.00-6.89 (m, 2H), 4.96 (s, 2H), 4.40 (q, J=7.1 Hz, 2H), 4.03-3,45 (br s, 1H), 3.21-3.01 (m, 2H), 1.41 (t, J=7.1 Hz, 3H), 1.31-1.07 (m, 4H), 0.95-0.76 (m, 3H).

    N-Benzyl-3-(butylamino)-4-phenoxy-5-sulfamoyl-benzamide (TEPS 2)

    [0397] ##STR00157##

    [0398] 3 mmol (1.09 g) of bumetanide were dissolved in 20 ml dichloromethane and 3.38 mmol (0.65 g) EDC.HCl were added. After 5 min 3.37 mmol (0.52 g) HOBt were added and the reaction mixture was stirred for another 5 min. Then 3 mmol (328 l) benzylamine were added and the reaction mixture was stirred at room temperature overnight. Once the reaction was completed, it was extracted three times with ethyl acetate and the combined organic layers were washed with brine and dried with Na.sub.2SO.sub.4. The solvent was then evaporated under reduced pressure and the crude product was purified by column chromatography (toluene/ethyl acetae 6+4) and by recrystallization from 50% ethanol. .sup.1H-NMR (200 MHz, chloroform-d): 7.55-7.45 (m, 2H), 7.40-7.20 (m, 7H), 7.14-7.02 (m, 1H), 6.96-6.80 (m, 3H), 5.09 (s, 2H), 4.59 (d, J=5.8 Hz, 2H), 3.07 (t, J=6.9 Hz, 2H), 1.49-1.30 (m, 2H), 1.23-1.01 (m, 2H), 0.79 (t, J=7.2 Hz, 3H).

    Methyl 3-(butylamino)-5-(dimethylsulfamoyl)-4-phenoxy-benzoate (TEPS 3)

    [0399] ##STR00158##

    [0400] 3 mmol (1.09 g) of bumetanide were dissolved in 5 mL DMF and 9.9 mmol (1.37 g) K.sub.2CO.sub.3 and 10 mmol (0.62 mL) methyl iodide were added. The reaction mixture was stirred for 5 hours and poured into ice water. The resulting precipitate was filtered off and the crude product was purified by column chromatography (toluene/ethyl acetate 8+2). 1H-NMR (200 MHz, chloroform-d): 7.95 (d, J=1.9 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.34-7.22 (m, 2H), 7.06 (t, J=7.3 Hz, 1H), 6.83 (d, J=7.9 Hz, 2H), 3.94 (s, 3H), 3.69 (s, 1H), 3.10 (t, J=6.9 Hz, 2H), 2.79 (s, 6H), 1.52-1.35 (m, 2H), 1.26-1.06 (m, 2H), 0.82 (t, J=7.2 Hz, 3H).

    3-(Butylamino)-5-(dimethylsulfamoyl)-4-phenoxy-benzoic Acid (TEPS 4)

    [0401] ##STR00159##

    [0402] 3 mmol (1.09 g) of bumetanide were dissolved in 20 mL of dichloromethane, then 3.38 mmol (0.65 g) EDC.HCl were added. After 5 min 3.37 mmol (0.52 g) HOBt were added and the reaction mixture was stirred for 5 min. Then 3.01 mmol (274 l) of aniline were added and the reaction was stirred at room temperature overnight. The mixture was then extracted with ethyl acetate and washed with saturated NaHCO.sub.3 solution and dried with Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure and the crude product was recrystallized from EtOH to yield 3-(butylamino)-4-phenoxy-N-phenyl-5-sulfamoyl-benzamide. 0.3 mmol (0.265 g) of 3-(butylamino)-4-phenoxy-N-phenyl-5-sulfamoyl-benzamide were dissolved in 4 mL methanol and 2 mL THF. Then 2 mL of 1M LiOH solution were added and the mixture was stirred at room temperature until the reaction was completed. The reaction mixture was acidified with 2M HCl and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried with Na.sub.2SO.sub.4. The solvent was then evaporated under reduced pressure. .sup.1H-NMR (200 MHz, chloroform-d): 8.05 (d, J=2.0 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.37-7.24 (m, 2H), 7.07 (t, J=7.3 Hz, 1H), 6.91-6.79 (m, 2H), 3.13 (t, J=6.9 Hz, 2H), 2.81 (s, 6H), 1.53-1.37 (m, 2H), 1.29-1.08 (m, 2H), 0.83 (t, J=7.2 Hz, 3H).

    3-(Butylamino)-5-(chloromethyl)-2-phenoxy-benzenesulfonamide (TEPS 76)

    [0403] ##STR00160##

    [0404] 1 mmol (0.35 g) of 3-(butylamino)-5-(hydroxymethyl)-2-phenoxy-benzenesulfonamide (Toellner K et al., Annals of Neurology (2014), 75(4), 550-562) was dissolved in 5 mL of thionyl chloride and heated to 80 C. for three hours. The thionyl chloride was evaporated under reduced pressure and the substance was vacuum-dried for one hour. The product was purified by recrystallization from 70% MeOH, yielding 0.34 g of brown crystals (92% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.43-7-27 (m, 3H), 7.08 (t, J=7.3 Hz, 1H), 7.02-6.79 (m, 3H), 4.88 (s, 2H) 4.57 (s, 2H), 3.07 (t, J=6.9 Hz, 2H), 1.54-1.33 (m, 2H), 1.28-1.08 (m, 2H), 0.83, J=7.1 Hz (t, 3H). MS m/z: 368/370 M.sup.+

    3-(Butylamino)-2-phenoxy-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide (TEPS 5)

    [0405] ##STR00161##

    [0406] General Procedure A:

    [0407] 1 mmol (369 mg) of 3-(butylamino)-5-(chloromethyl)-2-phenoxy-benzenesulfonamide (TEPS 76) was dissolved in 3 mL dimethylformamide (DMF). To this 2 mmol (157 l) of 2,2,2-trifluoroethylamine were added and the mixture was stirred at room temperature overnight. After the reaction was completed, which was verified by thin layer chromatography, the fluid was evaporated under reduced pressure, yielding a white crude product. This crude product was purified by column chromatography (ethyl acetate/petroleum ether 6+4) and recrystallization from 70% MeOH, yielding 130 mg of white crystals (30% yield). .sup.1H NMR (200 MHz, Methanol-d4) 7.34-7.18 (m, 3H), 7.09-6.96 (m, 2H), 6.94-6.83 (m, 2H), 3.90 (s, 2H), 3.29-3.17 (m, 2H), 3.09 (t, J=6.8 Hz, 2H), 1.49-1.32 (m, 2H), 1.26-1.06 (m, 2H), 0.81 (t, J=7.2 Hz, 3H). MS m/z: 431 M.sup.+

    3-(Butylamino)-5-(morpholinomethyl)-2-phenoxy-benzenesulfonamide (TEPS 6)

    [0408] ##STR00162##

    [0409] TEPS 6 was prepared according to general procedure A, but instead of 2,2,2-trifluoroethylamine, 2 mL of morpholine were added. The crude product was purified by column chromatography (ethyl acetate/petroleum ether 1+1) and recrystallization from EtOH, yielding 130 mg of beige crystals (31% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.38-7.23 (m, 3H), 7.20-6.80 (m, 4H), 5.10 (s, 2H), 3.98-3.66 (m, 5H), 3.54 (s, 2H), 3.16-2.98 (m, 2H), 2.77-2.36 (m, 4H), 1.52-1.30 (m, 2H), 1.27-1.08 (m, 2H), 0.82 (t, J=7.1 Hz, 3H). MS m/z: 419 M.sup.+

    3-(Butylamino)-5-(1H-imidazol-2-ylsulfanylmethyl)-2-phenoxy-benzenesulfonamide (TEPS 7)

    [0410] ##STR00163##

    [0411] TEPS 7 was prepared according to general procedure A, but instead of 2,2,2-trifluoroethylamine, 1 mmol (100 mg) 2-mercaptoimidazole was added and the reaction was stirred for two days. The crude product was purified by column chromatography (ethyl acetate/petroleum ether/triethylamine 6+3+1) and recrystallization from 70% EtOH, yielding 0.22 g of white crystals (51% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.36-7.21 (m, 2H), 7.14 (s, 2H), 7.10-6.96 (m, 2H), 6.94-6.80 (m, 2H), 6.63 (d, J=2.0 Hz, 1H), 4.17 (s, 2H), 2.95 (t, J=6.8 Hz, 2H), 1.42-1.26 (m, 2H), 1.22-1.02 (m, 2H), 0.80 (t, J=7.2 Hz, 3H). MS m/z: 432 M.sup.+

    3-(Butylamino)-2-phenoxy-5-(pyrimidin-2-ylsulfanylmethyl)benzenesulfonamide (TEPS 8)

    [0412] ##STR00164##

    [0413] TEPS 8 was prepared according to general procedure A, but instead of 2,2,2-trifluoroethylamine, 1 mmol (112 mg) of 2-mercaptopyrimidine were added. The crude product was purified by column chromatography (ethyl acetate/petroleum ether 7+3) and recrystallization from 70% MeOH, yielding 210 mg of white crystals (47% yield). .sup.1H NMR (200 MHz, chloroform-d) 8.55 (d, J=4.8 Hz, 2H), 7.38 (d, J=1.8 Hz, 1H), 7.35-7.23 (m, 2H), 7.18-6.83 (m, 5H), 4.90 (s, 2H), 4.41 (s, 2H), 3.80 (t, J=5.3 Hz, 1H), 3.17-2.91 (m, 2H), 1.49-1.31 (m, 2H), 1.26-1.05 (m, 2H), 0.81 (t, J=7.1 Hz, 3H). MS m/z: 444 M.sup.+

    3-(Butylamino)-5-[(1-methylimidazol-2-yl)sulfanylmethyl]-2-phenoxy-benzenesulfonamide (TEPS 9)

    [0414] ##STR00165##

    [0415] TEPS 9 was prepared according to general procedure A, but instead of 2,2,2-trifluoroethylamine, 1 mmol (114 mg) of 2-mercapto-1-methylimidazole was added. The crude product was purified by column chromatography (ethyl acetate/petroleum ether/triethylamine 6+3+1) and recrystallization from 70% MeOH, yielding 180 mg of white crystals (40% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.33-7.08 (m, 5H), 7.07-6.91 (m, 3H), 6.81 (d, J=7.7 Hz, 2H), 6.65 (d, J=1.7 Hz, 1H), 4.75, (t, J=5.7 Hz, 1H), 4.17 (s, 2H), 3.43 (s, 3H), 2.98-2.81 (m, 2H), 2.98-2.81 (m, 2H), 1.17-0.99 (m, 2H), 0.77 (t, J=7.1 Hz, 3H). MS m/z: 446 M.sup.+

    3-(Butylamino)-5-(1-hydroxy-1-methyl-ethyl)-2-phenoxy-benzenesulfonamide (TEPS 10)

    [0416] ##STR00166##

    [0417] To a solution of 4 mmol of methyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate (WO 2013/087090) in 10 mL dry THF 15 mL of methylmagnesium bromide solution (1.4 M in THF) were added and the mixture was stirred at room temperature. In 30 min intervals another 3 mL of the methylmagnesium bromide solution (1.4 M in THF) were added each time for 5 times. After stirring for three hours in total the mixture was quenched with 5% aqueous NH.sub.4Cl which caused a white solid to precipitate. The mixture was then extracted with ethyl acetate and washed twice with water and once with brine. The organic layer was dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (EtOAc/petroleum ether 1+1) and recrystallization from 70% EtOH yielding 1.06 g of a brown solid (70% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.40-7.21 (m, 3H), CH (aromatic), 7.17-6.99 (m, 2H), 6.99-6.83 (m, 2H), 5.07 (s, 2H), 3.78 (t, J=5.1 Hz, 1H), 3.16-2.97 (m, 2H), 2.33 (s, 1H), 1.57 (s, 6H), 1.49-1.32 (m, 2H), 1.29-1.10 (m, 2H), 0.81 (t, J=7.1 Hz, 3H). MS m/z: 378 M.sup.+

    3-(Butylamino)-5-isopropenyl-2-phenoxy-benzenesulfonamide (TEPS 11)

    [0418] ##STR00167##

    [0419] 0.5 mmol of TEPS 10 were dissolved in 5 mL thionyl chloride and the mixture was stirred for one day. After the reaction was completed, the thionyl chloride was evaporated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether 1+1) and recrystallization from 70% EtOH, yielding 120 mg of a beige solid (67% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.44-7.27 (m, 3H), 7.12-6.90 (m, 4H), 5.39 (s, 1H), 5.23-5.10 (m, 1H), 4.89 (s, 2H), 3.78 (t, J=5.3 Hz, 1H), 3.16-3.00 (m, 2H), 2.17 (s, 3H), 1.51-1.35 (m, 2H), 1.24-1.11 (m, 2H), 0.83 (t, J=7.2 Hz, 3H). MS m/z: 360 M.sup.+

    3-(Butylamino)-5-[(4-hydroxy-4-phenyl-1-piperidyl)methyl]-2-phenoxy-benzenesulfonamide (TEPS 12)

    [0420] ##STR00168##

    [0421] TEPS 12 was prepared according to general procedure A, but instead of 2,2,2-trifluoroethylamine, 1.2 mmol (213 mg) of 4-hydroxy-4-phenylpiperidine were added and the mixture was stirred at room temperature for two days. The crude product was purified by column chromatography (EtOAc/petroleum ether 1+1) and recrystallization from 70% MeOH, yielding 210 mg of white crystals (41% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.64-7.46 (m, 2H), 7.41-7.25 (m, 6H), 7.16-6.85 (m, 4H), 4.95 (s, 2H), 5.21-4.72 (m, 1H), 3.57 (s, 2H), 5=3.20-2.99 (m, 2H), 2.97-2.72 (m, 2H), 2.53 (t, J=10.8 Hz, 2H), 2.32-2.02 (m, 2H), 1.88-1.61 (m, 3H), 1.51-1.32 (m, 2H), 1.28-1.12 (m, 2H), 0.83 (t, J=7.1 Hz, 3H). MS m/z: 510 M.sup.+

    3-(Butylamino)-5-[(cyanomethylamino)methyl]-2-phenoxy-benzenesulfonamide (TEPS 13)

    [0422] ##STR00169##

    [0423] TEPS 13 was prepared according to general procedure A, but instead of 2,2,2-trifluoroethylamine, 1.2 mmol (167 l) triethylamine and 1.2 mmol (71 l) of aminoacetonitrile were added. The crude product was purified by column chromatography (EtOAc/petroleum ether 1+1) and recrystallization from 70% EtOH yielding 180 mg of beige powder (46% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.40-7.22 (m, 3H), 7.16-6.85 (m, 4H), 5.02 (s, 2H), 3.91 (s, 2H), 3.88-3.78 (m, 1H), 3.60 (s, 2H), 3.20-3.00 (m, 2H), 2.99-2.83 (d, 1H), 1.49-1.34 (m, 2H), 1.26-1.12 (m, 2H), 0.90-0.74 (m, 3H). MS m/z: 388 M.sup.+

    3-(Butylamino)-2-phenoxy-5-[(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)methyl]benzenesulfonamide (TEPS 14)

    [0424] ##STR00170##

    [0425] TEPS 14 was prepared according to general procedure A, but instead of 2,2,2-trifluoroethylamine, 1.2 eq. 4-phenyl-1,2,3,6-tetrahydropyridine was added. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether 3+7) to yield 110 mg of TEPS 14 (29.3% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.54-7.21 (m, 9H), 7.07 (t, J=7.5 Hz, 1H), 7.00-6.83 (m, 2H), 6.07 (s, 1H), 5.06 (s, 2H), 4.00-3.72 (m, 3H), 3.50-3.28 (m, 2H), 3.17-3.03 (m, 2H), 3.00-2.80 (m, 2H), 2.80-2.56 (m, 2H), 1.54-1.32 (m, 2H), 1.28-1.06 (m, 2H), 0.81 (t, J=7.1 Hz, 3H). MS m/z: 491 M.sup.+

    N-[3-(Butylamino)-2-phenoxy-5-[(2-thienylmethylamino)methyl]phenyl]sulfonyl-N,N-dimethyl-formamidine Hydrochloride (TEPS 15)

    [0426] ##STR00171##

    [0427] 3-(Butylamino)-2-phenoxy-5-[(2-thienylmethylamino)methyl]benzenesulfonamide was prepared according to the general procedure A, but instead of aniline, 1 mmol (104 l) of 2-Thiophenemethylamine was added. The crude product was purified by column chromatography (ethyl acetate/petroleum ether 1+1) and recrystallization from 70% EtOH, yielding 0.23 g of beige crystals (52% yield). 0.22 mmol (0.100 g) of 3-(butylamino)-2-phenoxy-5-[(2-thienylmethylamino)methyl]benzenesulfonamide were dissolved in 5 mL of dry THF and 0.48 mmol (0.068 mL) DMF-DMA were added. The reaction was stirred overnight and purified by column chromatography (ethyl acetate). The resulting brown solid was then dissolved in dry THF and 3 mL of HCl 1M in diethyl ether was added. The participating HCl salt was filtered off to yield beige crystals (37.5% yield). .sup.1H NMR (200 MHz, chloroform-d) 10.36 (s, 1H), 7.91 (s, 1H), 7.49 (d, J=11.9 Hz, 3H), 7.37-7.20 (m, 3H), 7.11-6.70 (m, 4H), 4.30 (s, 2H), 4.10 (s, 2H), 3.74 (t, J=6.6 Hz, 1H), 3.13 (s, 2H), 2.70 (d, J=43.2 Hz, 6H), 2.00-1.70 (m, 1H), 1.47-1.25 (m, 2H), 1.23-1.00 (m, 2H), 0.76 (t, J=6.9 Hz, 3H).

    Methyl 3-(butylamino)-5-[2-(dimethylamino)ethylsulfamoyl]-4-phenoxy-benzoate (TEPS 16)

    [0428] ##STR00172##

    [0429] 0.19 mmol (0.087 g) of methyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate (WO 2013/087090) were dissolved in 5 mL of DMF and 1.3 mmol (0.188 g) 2-Dimethylaminoethylchlorid.HCl and 2.2 mmol (0.304 g) K.sub.2CO.sub.3 were added. The reaction was stirred at 40 C. for two days and the resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether/triethylamine 3+6.5+0.5) to yield white powder (39.6% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.95 (d, J=1.8 Hz, 1H), 7.67-7.53 (m, 1H), 7.29 (t, J=7.7 Hz, 2H), 7.06 (t, J=7.3 Hz, 1H), 6.88 (d, J=7.8 Hz, 2H), 3.93 (s, 3H), 3.88 (s, 1H), 3.26-3.07 (m, 2H), 3.05-2.90 (m, 2H), 2.44-2.29 (m, 2H), 2.16 (s, 6H), 1.51-1.35 (m, 2H), 1.21-1.05 (m, 2H), 0.81 (t, J=7.1 Hz, 3H). MS m/z: 449 M.sup.+

    Methyl 3-(butylamino)-5-[2-(dimethylamino)ethylsulfamoyl]-4-phenoxy-benzoate (TEPS 17)

    [0430] ##STR00173##

    [0431] TEPS 16 was dissolved in dry THF and 3 mL of HCl 1M in diethyl ether was added. The participating HCl salt was filtered off to yield white powder (92.5% yield). .sup.1H NMR (200 MHz, chloroform-d) 11.28 (s, 1H), 7.88 (s, 1H), 7.56 (s, 1H), 7.33-7.19 (m, 3H), 7.02 (t, J=8.1 Hz, 2H), 3.93 (s, 3H), 3.31 (d, J=22.4 Hz, 4H), 3.09 (t, J=6.8 Hz, 2H), 2.83 (s, 6H), 1.52-1.32 (m, 2H), 1.28-1.07 (m, 2H), 0.81 (t, J=7.1 Hz, 3H).

    5-(Anilinomethyl)-3-(butylamino)-N-[2-(dimethylamino)ethyl]-2-phenoxy-benzenesulfonamide (TEPS 18)

    [0432] ##STR00174##

    [0433] 0.5 mmol (0.213 g) of 5-(anilinomethyl)-3-(butylamino)-2-phenoxy-benzenesulfonamide (Lykke K et al., British Journal of Pharmacology (2015), 172(18), 4469-4480) were dissolved in 5 mL of DMF and 2 mmol (0.288 g) 2-Dimethylaminoethylchlorid.HCl and 2 mmol (0.278 g) K.sub.2CO.sub.3 were added. The reaction was stirred at 40 C. overnight and the resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether/triethylamine 3+6.5+0.5) to yield brown solid (38.3% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.42-7.09 (m, 6H), 7.08-6.84 (m, 4H), 6.83-6.58 (m, 3H), 5.33 (s, 1H), 4.33 (s, 2H), 3.83 (t, J=5.3 Hz, 1H), 3.13-3.00 (m, 2H), 2.99-2.87 (m, 2H), 2.38-2.27 (m, 2H), 2.17 (s, 6H), 1.41-1.27 (m, 2H), 1.19-1.03 (m, 2H), 0.79 (t, J=7.1 Hz, 3H). MS m/z: 496 M.sup.+

    3-(Butylamino)-5-(ethoxymethyl)-2-phenoxy-benzenesulfonamide (TEPS 19)

    [0434] ##STR00175##

    [0435] 0.27 mmol (100 mg) of TEPS 76 were dissolved in acetonitrile and 0.44 mmol (34 l) sodium ethoxide were added. The reaction mixture was stirred at room temperature overnight and then additional 0.15 mmol (12 l) of sodium ethoxide were added. After the reaction was completed 5% aqueous NaHCO.sub.3 solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by recrystallization from EtOH yielding 38 mg of a brown solid (22.7% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.39-7.23 (m, 3H), 7.20-6.80 (m, 4H), 4.92 (s, 2H), 4.49 (s, 2H), 3.59 (q, J=7.0 Hz, 2H), 3.05 (t, J=7.0 Hz, 2H), 1.52-1.33 (m, 2H), 1.27 (t, J=7.0 Hz, 3H), 1.23-1.05 (m, 2H), 0.81 (t, J=6.8 Hz, 3H). MS m/z: 378 M.sup.+

    3-(Butylamino)-2-phenoxy-5-(phenoxymethyl)benzenesulfonamide (TEPS 20)

    [0436] ##STR00176##

    [0437] 0.64 mmol (60 mg) of Phenol were dissolved in 5 mL of DMF and 0.54 mmol (200 mg) of TEPS 76 were added in three portions over 15 min. The reaction was stirred at room temperature overnight. After the reaction was completed 5% aqueous NaHCO.sub.3 solution was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether3+7) to yield 43 mg of TEPS 20 (15.6% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.62-7.20 (m, 6H), 7.19-6.83 (m, 6H), 5.04 (s, 2H), 4.94 (s, 2H), 3.04 (t, J=6.8 Hz, 2H), 1.53-1.30 (m, 2H), 1.29-1.01 (m, 2H), 0.81 (t, J=6.0 Hz, 3H). MS m/z: 426 M.sup.+

    3-(Butylamino)-2-phenoxy-5-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)benzenesulfonamide (TEPS 21)

    [0438] ##STR00177##

    [0439] 1 mmol (364 mg) bumetanide and 1.1 mmol (179 mg) of CDI were added to dry THF. Once a clear solution was formed 1.3 mmol (200 mg) 4-phenyl-1,2,3,6-tetrahydropyridine were added and the reaction was stirred at room temperature overnight. After the reaction was completed 5% aqueous NaHCO.sub.3 solution was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was recrystallized from EtOH to yield 294 mg of white powder (58% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.59-7.21 (m, 8H), 7.20-6.79 (m, 4H), 6.39-5.78 (m, 1H), 5.16 (s, 2H), 4.47-4.07 (m, 2H), 4.02-3.61 (m, 2H), 3.05 (t, J=6.8 Hz, 2H), 2.63 (s-br, 2H), 1.52-1.29 (m, 2H), 1.29-1.03 (m, 2H), 0.80 (t, J=7.1 Hz, 3H). MS m/z: 505 M.sup.+

    3-(Butylamino)-5-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxymethyl]-2-phenoxy-benzenesulfonamide (TEPS 22)

    [0440] ##STR00178##

    [0441] 0.27 mmol (100 mg) of TEPS 76 were dissolved in 3 mL of dry THF, then 22 mg of NaH and 63 l of tetraethyleneglykole were added. After the reaction was completed 5% aqueous NaHCO.sub.3 solution was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried with Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether 3+7) to yield 40 mg of TEPS 22 (27% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.28-7.14 (m, 3H), 7.06-6.73 (m, 4H), 5.19 (s, 2H), 4.46 (s, 2H), 3.86-3.39 (m, 14H), 3.27 (m, 2H), 2.97 (t, J=6.8 Hz, 2H), 1.54-0.97 (m, 7H), 0.74 (t, J=7.2 Hz, 3H). MS m/z: 540 M.sup.+

    3-(Butylamino)-4-phenoxy-5-sulfamoyl-N-(2,2,2-trifluoroethyl)benzamide (TEPS 23)

    [0442] ##STR00179##

    [0443] To a solution of 1 mmol (364 mg) of Bumetanide in 5 mL dry THF 1.2 mmol (194 mg) of 1,1-Carbonyldiimidazole (CDI) were added and the mixture was stirred for two hours. Once TLC did not show any bumetanide remaining, 2 mmol (157 l) of trifluoroethylamine were added and the mixture was stirred at room temperature overnight. Once the reaction was completed it was poured into 20 mL of 5% NaHCO.sub.3 and extracted with ethyl acetate. The organic phase was then dried over Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. The crude product was then purified by recrystallization from EtOH to yield 159 mg of white powder (36% yield). .sup.1H NMR (200 MHz, Methanol-d.sub.4) 7.73 (d, J=2.1 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H), 7.38-7.20 (m, 2H), 7.14-6.98 (m, 1H), 6.98-6.86 (m, 2H), 4.10 (q, J=9.3 Hz, 2H), 3.13 (t, J=6.8 Hz, 2H), 1.56-1.34 (m, 2H), 1.30-1.03 (m, 3H), 0.82 (t, J=7.2 Hz, 3H). MS m/z: 445 M.sup.+

    4-Morpholino-3-nitro-5-sulfamoyl-benzoic Acid (TEPS 24)

    [0444] ##STR00180##

    [0445] 1 mmol (280 mg) of 4-Chloro-3-nitro-5-sulfamoylbenzoic acid were dissolved in 2 mL morpholine and stirred under reflux overnight. Once the reaction was completed the crude product was purified by recrystallization from water to yield 222 mg of yellow crystals (67% yield). .sup.1H NMR (200 MHz, DMSO-d.sub.6) 14.02 (s, 1H), 8.86-8.71 (m, 1H), 8.61-8.43 (m, 1H), 7.69 (s, 2H), 4.18-3.57 (m, 4H), 3.28-3.07 (m, 4H).

    Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-4-(prop-2-ynylamino)benzoate (TEPS 25)

    [0446] ##STR00181##

    [0447] 1 mmol (350 mg) of TEPS 28 was dissolved in 5 mL Acetonitrile and 2 mmol (276 mg) of K.sub.2CO.sub.3 and 1.1 mmol (70 l) of propargylamine were added. The mixture was stirred overnight and after TLC showed no TEPS 28 remaining it was extracted with ethyl acetate and washed with brine. The combined organic layers were evaporated under reduced pressure and the resulting brown solid was recrystallized from 70% ethanol to yield 108 mg of brown crystals (30% yield). .sup.1H NMR (200 MHz, DMSO-d.sub.6) 8.53-8.39 (m, 2H), 8.31 (s, 1H), 7.29 (t, J=5.6 Hz, 1H), 4.31-4.07 (m, 2H), 3.85 (s, 3H), 3.32 (s, 1H), 3.26 (t, J=2.3 Hz, 1H), 3.15 (s, 1H), 2.94 (s, 1H).

    Methyl 3-(dibutylamino)-4-phenoxy-5-sulfamoyl-benzoate (TEPS 26) (WO 2013/087090)

    [0448] ##STR00182##

    [0449] 2 mmol (228 l) of butyraldehyde was added to a solution of 1 mmol of methyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate (WO 2013/087090) in 10 mL 1,2-dichlorethane. To this solution 1.5 mmol (87 l) of acetic acid was added. The reaction mixture was cooled to 0 C. and 3 mmol (0.64 g) of sodium triacetoxyborohydride (NaBH(OAc)3) were added over 2 hours and the mixture was stirred overnight. After the reaction was completed 10 mL of water was added and it was stirred for one hour. The reaction mixture was extracted with 20 mL dichloromethane and washed with brine. Then the organic phase was dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/petroleum ether 7+3) and recrystallized from EtOH, yielding 223 mg of white crystals (51% yield). .sup.1H NMR (200 MHz, chloroform-d) 8.23 (d, J=1.2 Hz, 1H), 7.87 (s, 1H), 7.37-7.15 (m, 2H), 7.14-6.97 (m, 1H), 6.93-6.73 (m, 2H), 4.99 (s, 2H), 4.12-3.79 (m, 3H), 3.02 (t, J=7.2 Hz, 4H), 1.35-1.09 (m, 4H), 1.10-0.92 (m, 4H), 0.77 (t, J=6.8 Hz, 6H). MS m/z: 434 M.sup.+

    3-(Dibutylamino)-5-(hydroxymethyl)-2-phenoxy-benzenesulfonamide (TEPS 27) (WO 2013/087090)

    [0450] ##STR00183##

    [0451] 1 mmol of TEPS 26 was dissolved in 5 mL anhydrous THF and stirred at room temperature under argon atmosphere. Then 2 mL of a 1 M DIBAL-H solution in toluene were added. After one, two, three and four hours, respectively, another 1 mL of the 1M DIBAL-H solution in toluene were added each time and the reaction was stirred overnight. After TLC showed no remaining TEPS 26 the mixture was cooled to 0 C. and quenched with 5% aqueous NHCI4 solution causing a gel-like substance to precipitate. The precipitate was then dissolved in 2 N HCl and extracted three times with ethyl acetate. The combined organic layers were washed three times with water, once with brine and dried over Na2SO4. The fluids were evaporated under reduced pressure and purified by recrystallization from ethanol to yield 360 mg of beige powder (89% yield). .sup.1H NMR (200 MHz, Methanol-d.sub.4) 7.63 (brs, 1H), 7.40 (brs, 1H), 7.32-7.14 (m, 2H), 7.00 (t, J=7.3 Hz, 1H), 6.82 (d, J=7.5 Hz, 2H), 5 4.66 (s, 2H), 3.13 (t, J=7.4 Hz, 4H), 1.43-0.92 (m, 8H), 0.78 (t, J=7.0 Hz, 6H). MS m/z: 406 M.sup.+

    3-(Butylamino)-5-[(N-butylanilino)methyl]-2-phenoxy-benzenesulfonamide (TEPS 28)

    [0452] ##STR00184##

    [0453] 2 mmol (180 l) of butyraldehyde was added to a solution of 1 mmol of 5-(anilinomethyl)-3-(butylamino)-2-phenoxy-benzenesulfonamide (Lykke K et al., British Journal of Pharmacology (2015), 172(18), 4469-4480) in 10 mL 1,2-dichlorethane. To this solution 2 mmol (116 l) of acetic acid and 3 mmol (0.64 g) of sodium triacetoxyborohydride (NaBH(OAc).sub.3) were added and the mixture was stirred overnight. The mixture was then diluted with 10 mL water and 20 mL dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4 and then evaporated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether 7+3), yielding 312 mg of white powder (58% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.89 (s, 1H), 7.45-7.15 (m, 5H), 7.00 (t, J=7.3 Hz, 1H), 6.89-6.59 (m, 6H), 4.52 (s, 2H), 3.41 (t, J=7.6 Hz, 2H), 2.88 (t, J=7.0 Hz, 2H), 2.75 (s, 3H), 2.58 (s, 3H), 1.64 (s, 1H), 1.49-1.17 (m, 6H), 1.18-0.87 (m, 4H), 0.73 (t, J=7.2 Hz, 3H). MS m/z: 536 M.sup.+

    3-(Dibutylamino)-4-phenoxy-5-sulfamoyl-benzoic Acid (TEPS 29) (WO 2013/087090)

    [0454] ##STR00185##

    [0455] 1 mmol (434 mg) of TEPS 26 was dissolved in 3 mL of MeOH and 2 mL of 2N NaOH was added. The reaction was stirred at room temperature for two hours. After TLC showed no remaining TEPS 26 the solution was acidified with 2N HCl and the resulting precipitated was filtered off and dried under vacuum to yield 380 mg of white powder (90% yield). .sup.1H NMR (200 MHz, Methanol-d.sub.4) 8.22 (d, J=2.0 Hz, 1H), 7.91 (d, J=2.1 Hz, 1H), 7.37-7.15 (m, 2H), 7.02 (t, J=7.3 Hz, 1H), 6.83 (d, J=7.5 Hz, 2H), 3.10 (t, J=7.2 Hz, 4H), 1.38-1.15 (m, 4H), 1.13-0.93 (m, 4H), 0.78 (t, J=7.1 Hz, 6H).

    Methyl 7-[(E)-dimethylaminomethyleneamino]sulfonyl-2-methyl-1-prop-2-ynyl-benzimidazole-5-carboxylate (TEPS 30)

    [0456] ##STR00186##

    [0457] 1 mmol of TEPS 25 (368 mg) was added to 15 mL of ethanol and 3 mL of dioxane, this mixture was heated to 85 C. and stirred until it was fully dissolved. Then 10 mmol of ammonium chloride (535 mg) in 6 mL water was added. 4 mmol of Iron powder (223 mg) was added in three portions 2 minutes apart. The reaction was stirred at 85 C. for another 2.5 hours until TEPS 25 could not be detected via TLC anymore. The mixture was cooled to 60 C. and then extracted three times with 25 mL of dichloromethane. The combined organic layers were washed with water and brine and dried over Na.sub.2SO.sub.4. The crude product was purified by flash chromatography (ethyl acetate) and recrystallization from methanol to yield 90 mg of white crystals (25% yield). .sup.1H NMR (200 MHz, chloroform-d) 8.56 (s, 1H), 8.48 (s, 1H), 8.16 (s, 1H), 5.80 (d, J=2.5 Hz, 2H), 3.95 (s, 3H), 3.15 (s, 3H), 3.12 (s, 3H), 2.85 (s, 3H), 2.38 (t, J=5.0, 2.5 Hz, 2H). MS m/z: 362 M.sup.+

    Methyl 4-(butylamino)-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-benzoate (TEPS 31)

    [0458] ##STR00187##

    [0459] To a suspension of 3 mmol (842 mg) 4-chloro-3-nitro-5-sulfamoylbenzoic acid in 3 mL H.sub.2O, 10.8 mmol (907 mg) NaHCO.sub.3 was added cautiously followed by 6 mmol (595 l) Butylamine. The resulting solution was stirred at 85 for 16 hours. After the reaction was completed, 10 mL H.sub.2O was added and then acidified by adding 2 N HCl. The mixture was then cooled and the precipitate was filtered off to yield 825 mg of white crystals (86.6% yield). .sup.1H NMR (200 MHz, chloroform-d) 8.56 (d, J=2.2 Hz, 1H), 8.43 (d, J=2.2 Hz, 1H), 8.10 (s, 1H), 7.03 (s, 1H), 3.89 (s, 3H), 3.18 (s, 3H), 3.05 (s, 3H), 3.02-2.90 (m, 2H), 1.77-1.57 (m, 2H), 1.55-1.35 (m, 2H), 0.93 (t, J=7.1 Hz, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3) 164.7, 159.1, 143.7, 136.8, 133.1, 132.2, 129.5, 116.1, 52.3, 46.6, 41.8, 35.8, 32.1, 19.9, 13.7. MS m/z: 387 M.sup.+

    Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(1-methylimidazol-2-yl)sulfanyl-5-nitro-benzoate (TEPS 32)

    [0460] ##STR00188##

    [0461] To 10 mL of Acetonitrile were added 3 mmol (1.05 g) of methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-benzoate (WO2012/018635) 3.3 mmol (376 mg) of 2-mercapto-1-methylimidazole and 6.6 mmol (910 mg) of K.sub.2CO.sub.3. The solution was stirred at room temperature overnight. When TLC showed no remaining methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-benzoate the reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried with Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude product was then purified by recrystallization from ethanol to yield 1.04 g of yellow crystals (81% yield). .sup.1H NMR (200 MHz, DMSO-d.sub.6) 8.66 (d, J=1.9 Hz, 1H), 8.34 (d, J=1.8 Hz, 2H), 7.28 (s, 1H), 6.87 (s, 1H), 3.91 (s, 3H), 3.51 (s, 3H), 3.10 (s, 3H), 2.92 (s, 3H). MS m/z: not found

    Methyl 3-amino-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(1-methylimidazol-2-yl)sulfanyl-benzoate (TEPS 33)

    [0462] ##STR00189##

    [0463] 1 mmol of TEPS 32 (428 mg) was added to 15 mL of ethanol and 3 mL of dioxane, this mixture was heated to 85 C. and stirred until it was fully dissolved. Then 10 mmol of ammonium chloride (535 mg) in 6 mL water was added. 4 mmol of Iron powder (223 mg) was added in three portions 2 minutes apart. The reaction was stirred at 85 C. for another 2.5 hours until TEPS 32 could not be detected via TLC anymore. The mixture was cooled to 60 C. and then extracted three times with 25 mL of dichloromethane. The combined organic layers were washed with water and brine and dried over Na.sub.2SO.sub.4. The crude product was purified by flash chromatography (ethyl acetate) to yield 290 mg of yellow solid (73% yield). .sup.1H NMR (200 MHz, DMSO-d.sub.6) 8.25 (s, 1H), 7.79 (d, J=1.9 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.27 (d, J=1.3 Hz, 1H), 6.93 (d, J=1.3 Hz, 1H), 6.07 (s, 2H), 3.85 (s, 3H), 3.54 (s, 3H), 3.10 (s, 3H), 2.85 (s, 3H). MS m/z: not possible EI-MS

    Methyl 3-(butylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(1-methylimidazol-2-yl)sulfanyl-benzoate (TEPS 34)

    [0464] ##STR00190##

    [0465] 2 mmol (228 l) of butyl iodide was added to a solution of 1 mmol of TEPS 33 in 10 mL 1,2-dichlorethane. To this solution 1.5 mmol (87 l) of acetic acid was added. Then 3 mmol (0.64 g) of sodium triacetoxyborohydride (NaBH(OAc).sub.3) were added over 2 hours and the mixture was stirred overnight. After the reaction was completed it was poured into 30 mL of water. The reaction mixture was extracted twice with 20 mL dichloromethane and the combined organic layers were washed with brine. Then the organic phase was dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate) yielding 234 mg of yellow powder (52% yield). .sup.1H NMR (200 MHz, chloroform-d) 8.16 (s, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.36 (d, J=1.8 Hz, 1H), 7.10 (d, J=1.4 Hz, 1H), 6.96 (d, J=1.4 Hz, 1H), 5.79 (s, 1H), 3.91 (s, 3H), 3.59 (s, 3H), 3.10 (d, J=17.3 Hz, 8H), 1.62-1.44 (m, 2H), 1.43-1.15 (m, 2H), 0.92 (t, J=7.2 Hz, 3H). MS m/z: 453 M.sup.+

    3-(Butylamino)-4-(1-methylimidazol-2-yl)sulfanyl-5-sulfamoyl-benzoic Acid (TEPS 35)

    [0466] ##STR00191##

    [0467] 1 mmol (454 mg) of TEPS 34 was dissolved in 3 mL of MeOH and 2 mL of 2N NaOH was added. The reaction was stirred at room temperature for two hours. After TLC showed no remaining TEPS 34 the solution was acidified with 2N HCl and the resulting precipitate was filtered off and and recrystallized from EtOH to yield 346 mg of yellow crystals (90% yield). .sup.1H NMR (200 MHz, Methanol-d.sub.4) 8.78 (s, 1H), 8.03 (dd, J=4.7, 1.7 Hz, 1H), 7.56 (s, 1H), 7.37 (s, 1H), 7.18 (s, 1H), 3.69 (s, 3H), 3.28-3.10 (m, 2H), 1.68-1.43 (m, 2H), 1.41-1.18 (m, 2H), 0.92 (t, J=6.9 Hz, 3H). MS: not possible in EI

    Methyl 4-(4,5-dihydrothiazol-2-ylsulfanyl)-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-benzoate (TEPS 36)

    [0468] ##STR00192##

    [0469] In a three-necked flask, 1 mmol methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-benzoate (350 mg) was dissolved in acetonitrile (10 mL). Then 1.2 mmol of 2-mercaptothiazoline (MW=119.21 g/mol; 143 mg) and 2 mmol of K.sub.2CO.sub.3 (MW=138 g/mol; 276 mg) were added to the flask. The reactive mixture was stirred at room temperature overnight. Water was added to the reaction and it was extracted three times with ethyl acetate washed with brine. The organic layers was dried with Na.sub.2SO.sub.4 and the solvent removed under reduced pressure. The crude product was then purified by column-chromatography (ethyl acetate/petroleum ether 7+3). The yield was 283 mg of a yellow, crystalline solid (78.0% yield).

    Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-4-(3-thienyl)benzoate (TEPS 39)

    [0470] ##STR00193##

    [0471] 1 mmol of methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-benzoate (320 mg) was dissolved in 3 mL of dioxane. Then 1.3 mmol (167 mg) of 3-thienyl-boronic acid, 3 mmol (414 mg) of potassium carbonate and 100 mg of tetrakis(triphenylphosphine)palladium(0) were added. The reaction vial was flooded with argon, heated to 90 C. and stirred overnight. Then the mixture was cooled to room temperature and diluted with ethyl acetate and washed with water and brine. The organic layer was dried with Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (ethyl acetate/petroleum ether 7+3) to yield 278 mg of brown solid (70% yield). .sup.1H NMR (200 MHz, chloroform-d) 9.13 (d, J=1.8 Hz, 1H), 8.46 (d, J=1.8 Hz, 1H), 7.60-7.29 (m, 2H), 7.22-7.07 (m, 2H), 4.01 (s, 3H), 2.90 (s, 3H), 2.84 (s, 3H). MS m/z: 398 M.sup.+

    Methyl 3-amino-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(3-thienyl)benzoate (TEPS 40)

    [0472] ##STR00194##

    [0473] 1 mmol of TEPS 39 (397 mg) was added to 15 mL of ethanol and 3 mL of dioxane and this mixture was heated to 85 C. and stirred until it was fully dissolved. Then 10 mmol of ammonium chloride (535 mg) in 6 mL water was added. 4 mmol of Iron powder (223 mg) was added in three portions 2 minutes apart. The reaction was stirred at 85 C. for another 2.5 hours until TEPS 39 could not be detected via TLC anymore. The mixture was cooled to 60 C. and then extracted three times with 25 mL of dichloromethane. The combined organic layers were washed with water and brine and dried over Na.sub.2SO.sub.4. The crude product was purified by flash chromatography (ethyl acetate/petroleum ether 7+3) to yield 334 mg of yellow solid (90% yield). .sup.1H NMR (200 MHz, chloroform-d) 8.43 (d, J=1.6 Hz, 1H), 7.73 (d, J=1.7 Hz, 1H), 7.47-7.35 (m, 2H), 7.18-7.02 (m, 2H), 3.93 (s, 3H), 2.88 (s, 3H), 2.84 (s, 3H). MS m/z: 367 M.sup.+

    Methyl 3-(butylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(3-thienyl)benzoate (TEPS 41)

    [0474] ##STR00195##

    [0475] 1 mmol (367 mg) of TEPS 40 is dissolved in 5 mL acetonitrile. Then 3 mmol (408 mg) of K.sub.2CO3 and 3 mmol (3418 l) of butyl iodide are added. The reaction mixture is stirred at 90 C. for two days. After the reaction is completed the reaction mixture is poured into 20 mL of water and extracted with ethyl acetate three times. The combined organic layers are washed with brine and dried with Na.sub.2SO.sub.4. The solvent is then evaporated under reduced pressure and the resulting crude product is purified by column chromatography (ethyl acetate/toluene 1+1) to yield 90 mg of white powder (21,0% yield). .sup.1H NMR (200 MHz, chloroform-d) 8.37 (d, J=1.6 Hz, 1H), 7.66 (d, J=1.7 Hz, 1H), 7.52-7.36 (m, 2H), 7.12 (s, 1H), 7.13-7.00 (m, 1H), 3.94 (s, 3H), 3.13-2.99 (m, 2H), 2.89 (s, 3H), 2.85 (s, 3H), 1.56-1.35 (m, 2H), 1.32-1.12 (m, 2H), 0.86 (t, J=7.2 Hz, 3H). MS m/z: 424 M.sup.+

    Methyl 3-(dibenzylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-(3-thienyl)benzoate (TEPS 42)

    [0476] ##STR00196##

    [0477] 1 mmol (367 mg) of TEPS 40 is dissolved in 5 mL Acetonitrile. Then 2 mmol (276 mg) of K.sub.2CO.sub.3 and 2 mmol (238 l) of benzyl bromide are added. The reaction mixture is stirred at 70 C. overnight. After the reaction is completed the reaction mixture is poured into 20 mL of water and extracted with ethyl acetate three times. The combined organic layers are washed with brine and dried with Na.sub.2SO.sub.4. The solvent is then evaporated under reduced pressure and the resulting crude product is purified by column chromatography (ethyl acetate/toluene 1.5+8.5) to yield 193 mg of white powder (35% yield). .sup.1H NMR (200 MHz, chloroform-d) 8.70 (d, J=1.7 Hz, 1H), 8.01 (d, J=1.7 Hz, 1H), 7.43-7.28 (m, 1H), 7.30-7.15 (m, 8H), 7.07 (s, 1H), 7.03-6.88 (m, 5H), 4.04-3.80 (m, 7H), 2.87 (s, 3H), 2.79 (s, 3H). MS m/z: 547 M.sup.+

    5-(Benzyloxymethyl)-3-(butylamino)-2-phenoxy-benzenesulfonamide (TEPS 43)

    [0478] ##STR00197##

    [0479] To 10 mL of dry THF were added 1.5 mmol (37 mg) of NaH and 1.1 mmol (114 l) of benzyl alcohol. The solution was stirred for 10 min and then 1 mmol (369 mg) of TEPS 76 were added. The reaction was stirred at room temperature overnight. When TLC showed no remaining TEPS 76, the reaction mixture was dried under reduced pressure and purified by column chromatography (ethyl acetate/petroleum ether 3+7) to yield 100 mg of white powder (22% yield). .sup.1H NMR (200 MHz, chloroform-d) 7.51-7.20 (m, 8H), 7.06 (t, J=7.4 Hz, 1H), 7.00-6.88 (m, 3H), 4.85 (s, 2H), 4.60 (s, 2H), 4.53 (s, 2H), 3.83 (s, 1H), 3.05 (t, J=6.9 Hz, 2H), 1.57-1.29 (m, 2H), 1.29-1.05 (m, 2H), 0.81 (t, J=7.2 Hz, 3H). MS m/z: 440 M.sup.+

    Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-4-pyrimidin-2-ylsulfanyl-benzoate (TEPS 44)

    [0480] ##STR00198##

    [0481] In a three-necked flask, 1 mmol methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-benzoate (350 mg) was dissolved in acetonitrile (10 mL). Then 1.2 mmol of 2-mercaptopyrimidine (MW=112.15 g/mol; 135 mg) and 2 mmol of K.sub.2CO.sub.3 (MW=138 g/mol; 276 mg) were added to the flask. The reactive mixture was stirred at room temperature overnight and controlled by thin layer chromatography (ethyl acetate/petroleum ether 7+3). The mixture was extracted three times with ethyl acetate and washed with water (215 mL) and brine (120 mL). The organic layer was dried with Na.sub.2SO.sub.4 and the solvent removed under reduced pressure. The crude product was then purified by column chromatography (ethyl acetate/petroleum ether 7+3). The yield was 408 mg of a yellow, crystalline solid (95.9% yield). .sup.1H NMR (200 MHz, DMSO-d.sub.6) 8.84 (d, J=1.9 Hz, 1H), 8.68 (d, J=1.9 Hz, 1H), 8.59 (d, J=4.8 Hz, 2H), 8.24 (d, J=2.6 Hz, 2H), 7.31 (d, J=4.9 Hz, 1H), 3.96 (s, 3H), 3.33 (s, 3H), 2.99 (s, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3) 163.6, 161.1, 154.1, 147.2, 133.0, 132.9, 128.3, 63.4, 53.3, 42.0, 36.2, 36.0. MS m/z: 426 M.sup.+

    Methyl 3-amino-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-pyrimidin-2-ylsulfanyl-benzoate (TEPS 45)

    [0482] ##STR00199##

    [0483] In a three-necked flask 0.96 mmol TEPS 44 (408 mg) were dissolved under reflux in 20 mL EtOH and 10 mL dioxane. Then 9.8 mmol NH.sub.4Cl (MW=53.49 g/mol; 524 mg) were dissolved in 12.5 mL H.sub.2O and were added to the reaction vial. After 5 minutes 3.84 mmol Fe.sup.2+ (MW=55.85 g/mol; 215 mg), divided into 3 portions, were added. The reactive mixture was then stirred for 1 h under reflux. EtOH and dioxane were removed under reduced pressure, before dichloromethane and H.sub.2O were added. The product was extracted in dichloromethane and the organic layer was washed with 215 mL H.sub.2O and brine. The organic layer was dried with Na.sub.2SO.sub.4 and dichloromethane was removed under reduced pressure. The crude product was then purified by column-chromatography (ethyl acetate/petroleum ether 7+3) to yield 144 mg of orange crystals (37.9% yield). .sup.1H NMR (200 MHz, DMSO-d.sub.6) 8.80 (s, 1H), 8.56 (d, J=4.8 Hz, 1H), 8.33 (d, J=4.7 Hz, 2H), 8.07 (d, J=2.0 Hz, 1H), 6.88 (t, J=4.8 Hz, 1H), 3.88 (s, 5H), 3.18 (s, 2H), 2.93 (d, J=12.3 Hz, 2H). .sup.13C NMR (50 MHz, DMSO) 164.8, 160.8, 157.8, 146.2, 143.8, 130.7, 122.0, 114.0, 66.3, 52.7, 41.1, 35.4. MS m/z:397 M.sup.+

    Methyl 3-(butylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-pyrimidin-2-ylsulfanyl-benzoate (TEPS 46)

    [0484] ##STR00200##

    [0485] In a round-bottom flask 0.36 mmol TEPS 45 (144 mg) were dissolved in DMF. After that 0.45 mmol K.sub.2CO.sub.3 (63 mg) and 0.45 mmol butyliodide (51.1 l) were added to the reaction vial. The reactive mixture was stirred at room temperature overnight. Then DMF was removed under reduced pressure. The product was extracted in ethyl acetate and the organic layer washed with H.sub.2O and brine. The crude product was purified by column-chromatography (ethyl acetate/petroleum ether 7+3), to yield 143 mg of orange crystals (87.9% yield). .sup.1H NMR (200 MHz, chloroform-d) 9.42 (d, J=1.9 Hz, 1H), 8.98 (s, 1H), 8.68-8.44 (m, 3H), 8.34 (s, 1H), 6.87 (t, J=4.9 Hz, 1H), 3.95 (s, 3H), 3.20 (s, 3H), 3.04 (s, 2H), 2.87 (t, J=7.5 Hz, 2H), 1.60 (t, J=7.9 Hz, 1H), 1.39 (dd, J=15.1, 7.0 Hz, 2H), 0.85 (t, J=7.2 Hz, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3) 166.0, 161.2, 159.2, 158.1, 146.4, 143.6, 131.0, 125.3, 123.6, 123.0, 113.8, 52.5, 41.6, 37.0, 35.6, 31.5, 22.2, 13.6. MS m/z: 451 M.sup.+

    3-(Butylamino)-4-pyrimidin-2-ylsulfanyl-5-sulfamoyl-benzoic Acid (TEPS 47)

    [0486] ##STR00201##

    [0487] In a round-bottomed flask 0.28 mmol TEPS 46 (136 mg) were dissolved in 20 mL MeOH and 7 mL 2N NaOH. The reactive mixture was stirred for 2 h at 50 C. MeOH was removed under reduced pressure. The aqueous layer was poured into a beaker and acidified with 2N HCl. The resulting precipitate was afterwards extracted with ethyl acetate. The organic layer was washed with H.sub.2O and brine and the solvent was removed under reduced pressure, to yield 104 mg of a beige powder (89% yield). .sup.1H NMR (200 MHz, DMSO-d.sub.6) 13.43 (s, 1H), 9.36-8.88 (m, 2H), 8.59 (d, J=4.9 Hz, 2H), 8.23 (d, J=1.9 Hz, 1H), 7.52 (s, 2H), 7.01 (t, J=4.8 Hz, 1H), 2.82 (t, J=7.2 Hz, 2H), 1.46 (q, J=7.6 Hz, 2H), 1.34-1.05 (m, 3H), 0.73 (t, J=7.2 Hz, 3H). .sup.13C NMR (50 MHz, DMSO) 166.2, 159.3, 158.5, 148.5, 143.6, 131.2, 126.0, 123.7, 121.7, 114.2, 35.8, 30.8, 21.4, 13.3. MS m/z: 382M.sup.+

    Methyl 3-(benzylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-pyrimidin-2-ylsulfanyl-benzoate (TEPS 83)

    [0488] ##STR00202##

    [0489] In a round-bottom flask 0.36 mmol TEPS 45 (144 mg) were dissolved in DMF and 0.43 mmol K.sub.2CO.sub.3 (MG=138 g/mol; 60 mg) and 0.43 mmol benzylbromide (MG=171.04 g/mol; 5=1.44 g/cm.sup.3; 51.3 l) were added to the reaction vial. The reactive mixture was stirred at room temperature overnight. The progress was controlled by thin-layer chromatography (ethyl acetate/petroleum ether 7+3) and DMF was removed under reduced pressure. The product was extracted in 215 mL ethylacetate and the organic layer washed with 215 mL H.sub.2O and 120 mL brine. The crude product was purified by column-chromatography (ethyl acetate/petroleum ether 7+3), to yield 144 mg of beige/brown crystals (82.4% yield). .sup.1H NMR (200 MHz, chloroform-d) 9.33 (d, J=1.9 Hz, 1H), 8.69 (s, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.44 (d, J=4.8 Hz, 2H), 8.34 (s, 1H), 7.23-7.00 (m, 5H), 6.81 (t, J=4.8 Hz, 1H), 4.12 (s, 2H), 3.95 (s, 3H), 3.11 (s, 3H), 3.02 (s, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3) 166.0, 161.3, 159.1, 157.9, 146.8, 144.4, 136.7, 131.5, 129.1, 128.6, 127.3, 123.4, 123.1, 113.9, 52.6, 41.9, 41.6, 35.8, 29.8. MS m/z: 485 M.sup.+

    3-(Benzylamino)-4-pyrimidin-2-ylsulfanyl-5-sulfamoyl-benzoic Acid (TEPS 48)

    [0490] ##STR00203##

    [0491] In a round-bottom flask 0.28 mmol TEPS 83 (136 mg) were dissolved in 20 mL MeOH and 7 mL 2N NaOH. The reactive mixture was stirred for 2 h at 50 C. MeOH was removed under reduced pressure. The aqueous layer was poured into a beaker and acidified with 2N HCl. The resulting precipitate was afterwards extracted with ethyl acetate and washed with H.sub.2O and brine. The solvent was removed under reduced pressure, to yield 104 mg of a beige powder (89.2% yield). .sup.1H NMR (200 MHz, DMSO-d.sub.6) 9.10 (d, J=1.9 Hz, 1H), 8.80 (s, 1H), 8.54 (d, J=4.8 Hz, 2H), 8.23 (d, J=1.9 Hz, 1H), 7.58 (s, 2H), 7.24-6.92 (m, 5H), 4.09 (s, 2H). .sup.1C NMR (50 MHz, DMSO) 166.2, 158.8, 158.2, 149.0, 144.3, 136.5, 131.8, 128.9, 128.3, 127.1, 123.3, 122.8, 121.3, 114.2, 29.0. MS m/z: not possible in EI

    Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-4-prop-2-ynoxy-benzoate (TEPS 49)

    [0492] ##STR00204##

    [0493] 1.5 mmol (60 mg) NaH was rinsed with dry THF (6 mL) in three portions 5 minutes apart under argon atmosphere. After the dry THF was added for the third time, 1.1 mmol (64 l) propargylalcohol and 1 mmol (320 mg) methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-benzoate were added. The mixture was stirred at room temperature overnight. After the reaction was finished, which was controlled via thin layer chromatography, the mixture was extracted three times with ethyl acetate and washed with brine. The combined organic layers were evaporated under reduced pressure and the resulting orange solid was recrystallized from 96% ethanol to yield 83 mg of orange crystals (15% yield). .sup.1H NMR (200 MHz, chloroform-d) 8.96 (d, J=2.2 Hz, 1H), 8.70 (d, J=2.2 Hz, 1H), 8.33 (s, 1H), 5.04 (d, J=2.5 Hz, 2H), 3.98 (s, 3H), 3.23 (s, 3H), 3.04 (s, 3H), 2.69 (t, J=2.5 Hz, 1H). .sup.13C NMR (50 MHz, CDCl.sub.3) 163.7, 161.4, 151.7, 144.9, 139.9, 135.3, 130.5, 127.3, 77.8, 77.5, 64.7, 53.2, 42.0, 35.9. MS m/z: 370 M.sup.+

    Methyl 4-(allylamino)-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-benzoate (TEPS 50)

    [0494] ##STR00205##

    [0495] 1 mmol (320 mg) of methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-benzoate was dissolved in 5 mL Acetonitrile and 2 mmol (276 mg) of K.sub.2CO.sub.3 and 1.1 mmol (70 l) of allylamine were added. The mixture was stirred overnight and after TLC showed no methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-benzoate remaining it was extracted with ethyl acetate and washed with brine. The combined organic layers were evaporated under reduced pressure and the resulting yellow solid was recrystallized from 70% ethanol to yield 78 mg of yellow crystals (21.1% yield). .sup.1H NMR (200 MHz, chloroform-d) 8.59 (d, J=2.1 Hz, 1H), 8.46 (d, J=2.1 Hz, 1H), 8.10 (s, 1H), 7.15 (s, 1H), 6.04-5.71 (m, 1H), 5.49-5.30 (m, 1H), 5.29-5.18 (m, 1H), 3.90 (s, 3H), 3.69 (d, J=5.7 Hz, 2H), 3.18 (s, 3H), 3.04 (s, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3) 164.6, 159.1, 143.3, 137.3, 133.1, 132.8, 132.2, 130.3, 118.8, 116.9, 52.4, 49.1, 41.8, 35.9. MS m/z: 371 M.sup.+

    Methyl 4-anilino-3-nitro-5-sulfamoyl-benzoate (TEPS 51)

    [0496] ##STR00206##

    [0497] To a solution of 10 mmol (2.947 g) Methyl 3-(benzylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-phenylsulfanyl-benzoate in 50 mL acetonitrile 24 mmol aniline (2.191 mL) and 20 mmol K.sub.2CO.sub.3 (2.764 g) were added. The mixture was stirred for two hours at room temperature. After the reaction was complete, which was controlled by thin layer chromatography, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over Na.sub.2SO.sub.4 and then evaporated under reduced pressure. The resulting crude product was purified by recrystallization from EtOH (70%) yielding 3.40 g of orange crystals (97% yield). .sup.1H NMR (200 MHz, DMSO-d.sub.6) 8.60 (d, J=2.1 Hz, 1H), 8.46 (s, 1H), 8.41 (d, J=2.1 Hz, 1H), 8.11 (s, 2H), 7.37-7.22 (m, 2H), 7.09 (t, J=7.3 Hz, 1H), 7.03-6.89 (m, 2H), 3.90 (s, 3H).sup.13C NMR (50 MHz, DMSO) 163.8, 140.2, 139.3, 137.7, 133.9, 133.2, 131.1, 129.3, 124.5, 119.4, 119.3, 52.6. MS m/z: 351 M.sup.+

    Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-4-phenylsulfanyl-benzoate (TEPS 52)

    [0498] ##STR00207##

    [0499] To a solution of 2 mmol (700 mg) methyl 4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-benzoate in 10 mL acetonitrile 4 mmol K.sub.2CO.sub.3 (553 mg) and 2.4 mmol of thiophenol (245 l) were added. The mixture was stirred at room temperature for one day and after the reaction was finished, which was controlled via thin layer chromatography, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over Na.sub.2SO.sub.4 and then evaporated under reduced pressure. The resulting crude product was purified by column chromatography (first 300 mL of petroleum ether, then 300 mL of ethyl acetate) yielding 723 mg of yellow crystals (85% yield). .sup.1H NMR (200 MHz, chloroform-d) 9.10 (d, J=1.9 Hz, 1H), 8.36-8.25 (m, 2H), 7.34-7.18 (m, 3H), 7.16-7.03 (m, 2H), 3.98 (s, 3H), 2.96 (s, 3H), 2.87 (s, 3H).sup.13C NMR (50 MHz, CDCl.sub.3) 163.8, 161.3, 154.2, 147.0, 133.5, 132.6, 131.3, 129.90, 129.4, 128.4, 128.0, 77.2, 53.2, 41.6, 35.6. MS m/z: 423 M.sup.+

    Methyl 3-amino-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-phenylsulfanyl-benzoate (TEPS 53)

    [0500] ##STR00208##

    [0501] To a solution of 1 mmol (423 mg) TEPS 52 in 10 mL EtOH a solution of 10 mmol (535 mg) NH.sub.4Cl in 30 mL H.sub.2O was added. The mixture was stirred and heated under reflux. After adding 10 mL dioxane 4 mmol (223 mg) iron was added in three portions at intervals of three minutes. This mixture was heated for eight hours. After the reaction was complete, which was controlled via thin layer chromatography, the mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4 and then evaporated under reduced pressure, yielding 390 mg of light yellow crystals (99% of compound 4). .sup.1H NMR (200 MHz, chloroform-d) 8.39 (s, 1H), 8.22 (s, 1H), 7.65 (s, 1H), 7.26-7.06 (m, 3H), 6.99-6.84 (m, 2H), 4.25 (brs, 2H), 3.92 (s, 3H), 2.75 (s, 3H), 2.49 (s, 3H).sup.13C NMR (50 MHz, CDCl.sub.3) 165.9, 161.0, 150.1, 146.7, 134.7, 132.2, 129.3, 129.3, 125.7, 120.0, 119.9, 114.3, 77.2, 52.6, 41.2, 34.9. MS m/z: 493 M.sup.+

    Methyl 3-(butylamino)-5-[(E)-dimethylaminomethyleneamino]sulfonyl-4-phenylsulfanyl-benzoate (TEPS 54)

    [0502] ##STR00209##

    [0503] To a solution of 1.5 mmol (135 l) butyraldehyde in 10 mL 1,2 dichloroethane 1 mmol (393 mg) TEPS 53 was added. To this solution 1 mmol acetic acid (58 l) and 1.5 mmol (318 mg) sodium triacetoxyborohydride (NaBH(OAc).sub.3) were added and the mixture was stirred at room temperature overnight. After the reaction was complete, which was controlled via thin layer chromatography, the mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over Na.sub.2SO.sub.4 and then evaporated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether 1+1) yielding 60 mg of a beige powder (13% yield). .sup.1H NMR (200 MHz, chloroform-d) 8.31 (s, 1H), 8.22 (s, 1H), 7.49 (s, 1H), 7.33-7.04 (m, 3H), 7.01-6.83 (m, 2H), 3.93 (s, 3H), 3.11 (t, J=6.9 Hz, 2H), 2.74 (s, 3H), 2.49 (s, 3H), 1.51-1.28 (m, 2H), 1.21-0.98 (m, 2H), 0.77 (t, J=7.2 Hz, 3H).sup.13C NMR (50 MHz, CDCl.sub.3) 166.4, 161.0, 150.2, 146.7, 134.8, 132.3, 129.2, 129.2, 125.9, 125.8, 117.9, 114.8, 77.2, 52.6, 43.44, 41.1, 34.9, 31.0, 19.9, 13.7. MS m/z: 449 M.sup.+

    3-(Butylamino)-4-phenylsulfanyl-5-sulfamoyl-benzoic Acid (TEPS 55)

    [0504] ##STR00210##

    [0505] To a solution of 0.5 mmol (225 mg) TEPS 54 in 3 mL MeOH 2 mL 2N NaOH was added and stirred at room temperature overnight. When the reaction was complete, which was controlled by thin layer chromatography, the mixture was acidified with 2 mL 2N HCl. The precipitate was filtered off yielding 80 mg of a beige solid product (40% of compound 6). .sup.1H NMR (200 MHz, DMSO-d.sub.6) 7.86 (s, 1H), 7.45 (s, 2H), 7.35 (s, 1H), 7.31-7.06 (m, 4H), 5.53 (t, J=5.6 Hz, 1H), 3.20-2.98 (m, 2H), 1.41-1.18 (m, 3H), 1.12-0.88 (m, 2H), 0.72 (t, J=7.2 Hz, 3H).sup.13C NMR (50 MHz, DMSO) 166.7, 149.9, 148.8, 134.4, 133.1, 129.0, 127.4, 126.6, 114.9, 114.1, 113.5, 42.3, 39.9, 39.52, 39.1, 30.1, 19.1, 13.6. MS m/z: EI not possible

    Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-4-[[(1S)-2-methoxy-1-methyl-2-oxo-ethyl]amino]-5-nitro-benzoate (TEPS 56)

    [0506] ##STR00211##

    [0507] 3 mmol (1049 mg) of methyl-4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-benzoate and 6 mmol (839 mg) of L-alaninemethylester-hydrochloride were suspended in 15 mL N,N-dimethylformamide. To this mixture 1.5 mL of triethylamine were added and it was stirred at 100 C for 2 hours. After the reaction was completed, the solution was washed with water and extracted three times with ethyl acetate. The combined organic phases were washed with brine. The organic phase was dried over sodium sulfate and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether 7+3) and evaporated under reduced pressure yielding 2.21 mmol (920 mg) of yellow crystals (73.6% yield).

    [0508] [].sub.D.sup.20=+67.668 (c=0.5; Methanol)

    [0509] .sup.1H NMR (200 MHz, chloroform-d) 8.70 (d, J=2.1 Hz, 1H), 8.48 (d, J=2.3 Hz, 1H), 8.18 (s, 1H), 7.60 (d, J=7.8 Hz, 1H), 4.34-4.11 (m, 1H), 3.91 (s, 2H), 3.75 (s, 3H), 3.18 (s, 3H), 3.07 (s, 3H), 1.45 (d, J=6.9 Hz, 3H). MS m/z: 417 M.sup.+

    Methyl 3-[(E)-dimethylaminomethyleneamino]sulfonyl-4-[[(1R)-2-methoxy-1-methyl-2-oxo-ethyl]amino]-5-nitro-benzoate (TEPS 57)

    [0510] ##STR00212##

    [0511] 1 mmol (350 mg) of methyl-4-chloro-3-[(E)-dimethylaminomethyleneamino]sulfonyl-5-nitro-benzoate and 2 mmol (280 mg) of D-alaninemethylester hydrochloride were suspended in 10 mL N,N-dimethylformamide. To this mixture 1 mL of triethylamine were added and it was stirred at 100 C for 2 hours. After the reaction was completed, the solution was washed with water and extracted three times with ethyl acetate. The combined organic phases were washed with brine. The organic phase was dried over sodium sulfate and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate/petroleum ether 7+3) and evaporated under reduced pressure yielding 0.67 mmol (280 mg) of yellow crystals (67.0% yield).

    [0512] [].sub.D.sup.20=68.895 (c=0.5; Methanol)

    [0513] .sup.1H NMR (200 MHz, chloroform-d) 8.70 (d, J=2.1 Hz, 1H), 8.48 (d, J=2.2 Hz, 1H), 8.18 (s, 1H), 4.17 (dd, J=18.0, 7.0 Hz, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 3.18 (s, 3H), 3.07 (s, 3H), 1.45 (d, J=6.9 Hz, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3) 173.0, 164.6, 159.4, 141.9, 138.2, 134.0, 132.0, 131.7, 118.4, 53.5, 52.8, 52.6, 41.9, 36.0, 19.3. MS m/z: 417 M.sup.+

    Methyl (2S)-8-[(E)-dimethylaminomethyleneamino]sulfonyl-2-methyl-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylate (TEPS 58)

    [0514] ##STR00213##

    [0515] 2 mmol (833 mg) of TEPS 56 were solved in 15 mL ethanol. 2 mL of dioxane were added and the mixture was heated to 85 C. and stirred until it was fully dissolved. Then a solution of 24 mmol of ammonium chloride (1284 mg) in 6 mL water was added. 14 mmol of Iron powder (781 mg) was added in four portions 5 minutes apart. The mixture was cooled to 60 C. and then extracted three times with 25 mL of dichloromethane.

    [0516] The combined organic layers were washed with water and brine and dried over sodium sulfate. The filtrate was evaporated under reduced pressure and the resulting crude product was purified by column chromatography (with ethyl acetate/petroleum ether7+3 and ethyl acetate only) yielding 1.16 mmol (410 mg) of yellow crystals (57.8% yield).

    [0517] [].sub.D.sup.20=+15.353 (c=0.5; Methanol)

    [0518] .sup.1H NMR (200 MHz, DMSO-d.sub.6) 10.69 (s, 1H), 8.29 (s, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 6.63 (s, 1H), 4.19 (d, J=8.8 Hz, 1H), 3.80 (s, 3H), 3.13 (s, 3H), 2.91 (s, 3H), 1.25 (d, J=6.9 Hz, 3H). .sup.13C NMR (50 MHz, DMSO) 166.8, 165.2, 159.4, 134.6, 126.8, 124.2, 123.2, 117.7, 117.0, 51.9, 50.8, 40.8, 35.1, 29.0, 19.5. MS m/z: 354 M.sup.+

    3-(Butylamino)-2-phenoxy-5-(pyrrolidin-1-ylmethyl)benzenesulfonamide (TEPS 59)

    [0519] ##STR00214##

    [0520] 1 mmol (369 mg) of TEPS 76 was dissolved in 5 mL pyrrolidine and the mixture was stirred at room temperature overnight. After the reaction was completed, which was verified by thin layer chromatography, the fluid was evaporated under reduced pressure. The crude product was purified by column chromatography (toluene/triethylamine 8+2) and recrystallization from 70% EtOH, yielding 220 mg of white powder (55% yield). .sup.1H NMR (200 MHz, DMSO-d.sub.6) 7.39-6.62 (m, 9H), 4.67 (s, 1H), 3.56 (s, 2H), 3.14-2.91 (m, 2H), 2.30 (s, 1H), 1.84-1.61 (m, 4H), 1.52-1.24 (m, 2H), 1.27-1.00 (m, 2H), 0.77 (t, J=7.1 Hz, 3H). .sup.13C NMR (50 MHz, DMSO) 156.9, 142.0, 137.2, 137.0, 134.9, 129.0, 121.9, 115.5, 114.7, 113.7, 59.5, 53.6, 42.1, 30.4, 23.2, 19.3, 13.7. MS m/z: 403 M.sup.+

    3-(Butylamino)-5-(imidazole-1-carbonyl)-2-phenoxy-benzenesulfonamide (TEPS 60)

    [0521] ##STR00215##

    [0522] To a solution of 2.5 mmol (913 mg) of Bumetanide in 10 mL dry THF 2.75 mmol (447 mg) of 1,1-Carbonyldiimidazole (CDI) were added and the mixture was stirred at 67 C. for three hours. Then the mixture was cooled to room temperature and upon adding 15 mL of diethyl ether a white precipitate formed. The precipitate was filtered and dried under reduced pressure, yielding 0.98 g of white powder (94.30% yield). .sup.1H NMR (200 MHz,) 8.10 (d, J=1.4 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.29-7.12 (m, 4H), 7.08-6.69 (m, 3H), 3.00 (t, J=6.7 Hz, 2H), 1.41-1.23 (m, 2H), 1.19-0.93 (m, 2H), 0.70 (t, J=7.1 Hz, 3H). .sup.13C NMR (50 MHz, MeOH) 171.6, 158.4, 144.0, 141.1, 138.4, 133.3, 131.0, 124.3, 122.1, 117.7, 117.6, 117.1, 69.3, 44.2, 32.5, 21.3, 14.5.

    N-[3-(Butylamino)-5-(hydroxymethyl)-2-phenoxy-phenyl]sulfonyl-N,N-dimethyl-formamidine (TEPS 61)

    [0523] ##STR00216##

    [0524] To a solution of 1 mmol of 3-(butylamino)-5-(hydroxymethyl)-2-phenoxy-benzenesulfonamide (Toellner K et al., Annals of Neurology (2014), 75(4), 550-562) in 2.5 mL of DMF 1.2 mmol of (iodomethyl)cyclopropane and 1 mmol (124 mg) of AgO were added and stirred for two days. The mixture was then evaporated under reduced pressure and the resulting crude product was purified by column chromatography (toluene/triethylamine 8+2). According to the spectra the ether was not formed, but DMF bound to the sulfonamide-group resulting in the title compound, yielding 200 mg of yellow crystals (49% yield). .sup.1H NMR (200 MHz, DMSO-d.sub.6) 7.85 (s, 1H), 7.37-7.20 (m, 2H), 7.18-6.87 (m, 3H), 6.77-6.54 (m, 2H), 5.31 (t, J=5.8 Hz, 1H), 4.72-4.56 (m, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.20-3.93 (m, 1H), 3.06-2.94 (m, 2H), 2.86 (s, 3H), 1.42-1.25 (m, 2H), 1.16-1.00 (m, 2H), 0.75 (t, J=7.2 Hz, 3H). .sup.13C NMR (50 MHz, DMSO) =160.2, 156.3, 141.7, 140.3, 135.3, 134.5, 129.3, 121.9, 115.0. 113.0, 112.7, 62.7, 42.2, 40.7, 34.5, 30.4, 19.3, 13.6. MS m/z: 406 M.sup.+

    5-Chlorothiophene-2-carboxylic acid (TEPS 62) (Moni, L et al, 2016)

    [0525] ##STR00217##

    [0526] 300 mmol (12 g) NaOH were solved in 60 mL H.sub.2O and the solution was cooled down to 0-10 C. Then 90 mmol (4.65 mL) bromine were added. 30 mmol (4.8 g) 2-acetyl-5-chlorothiophene (T1) were solved in 30 mL dioxane and added at a temperature of 0-10 C. The solution was stirred for one hour at room temperature which caused that bromoform was built. Bromoform was removed by using a separatory funnel and 3 g sodium pyrosulfit in 45 mL H.sub.2O were added to the aqueous phase. The solution was acidified with conc. HCl whereas a beige precipitate was formed. The precipitate was collected by vacuum filtration with a yield of 3.72 g. (76.1%). .sup.1H NMR (200 MHz, chloroform-d) 7.69 (d, J=4.1 Hz, 1H), 7.26 (s, 1H), 6.98 (d, J=4.1 Hz, 1H).

    Methyl 5-chlorothiophene-2-carboxylate (TEPS 63) (Hauck, S. Et al, 2016)

    [0527] ##STR00218##

    [0528] 3.716 g (22.9 mmol) TEPS 62 were solved in 30 mL MeOH and 1.5 mL conc. H.sub.2SO.sub.4 were added. After 28 hours of stirring with reflux cooling, NaOH was added to alkalize the solution. Afterwards, the solution was extracted with ethyl acetate three times and dried over Na.sub.2SO.sub.4. Then the solvent was removed on a rotary evaporator, yielding a liquid brown product of 2.157 g (53.3%). .sup.1H NMR (200 MHz, chloroform-d) 7.59 (d, J=4.0 Hz, 1H) 6.93 (d, J=4.0 Hz, 1H) 3.87 (s, 3H). .sup.13C NMR (50 MHz, DMSO-d6) 160.8, 135.6, 133.8, 131.3, 128.6, 52.5. MS m/z: 176 M.sup.+

    Methyl 5-chloro-4-nitro-thiophene-2-carboxylate (TEPS 64) (Park, Chan L. Et al, 2014)

    [0529] ##STR00219##

    [0530] 12.2 mmol (2.157 g) TEPS 63 were solved in 3.9 mL conc. H.sub.2SO.sub.4, and then cooled down to 0-10 C. A 0-5 C. cold mixture of 3 mL conc. H.sub.2SO.sub.4 and 1.7 mL conc. HNO.sub.3 were added slowly and stirred for one hour at 0 C. Afterwards the mixture was poured on iced-water whereas a precipitate was formed. The precipitate was collected by vacuum filtration and washed three times, starting with H.sub.2O, following by 5% -sodiumhydrogencarbonat solution and again washed with H.sub.2O. The product was yellow with a yield of 1.502 g (54.9%). .sup.1H NMR (200 MHz, chloroform-d) 8.18 (s, 1H), 3.94 (s, 3H). .sup.13C NMR (50 MHz, chloroform-d) 128.6, 53.1. MS m/z: 221 M.sup.+

    Methyl 4-nitro-5-phenoxy-thiophene-2-carboxylate (TEPS 65) (Consiglio, G., et al, 2002)

    [0531] ##STR00220##

    [0532] 1.502 g (6.8 mmol) TEPS 64 were solved in 22.4 mL dimethylfomamide, then 0.694 g phenole and 1.86 g K.sub.2CO.sub.3 were added. The mixture was stirred overnight by room temperature. Afterwards H.sub.2O was added and the product was collected by extraction with ethyl acetate (three times). The organic layers were dried over Na.sub.2SO.sub.4 and the solvent was removed on a rotary evaporator, yielding 1.805 g of beige crystals (95.6%). .sup.1H NMR (200 MHz, chloroform-d) 8.11 (s, 1H) 7.64-7.16 (m, 5H) 3.85 (s, 3H). .sup.13C NMR (50 MHz, chloroform-d) 161.3, 156.8, 130.8, 128.3, 127.8, 120.0, 117.3, 52.9. MS m/z: 279 M.sup.+

    Methyl 4-amino-5-phenoxy-thiophene-2-carboxylate (TEPS 66)

    [0533] ##STR00221##

    [0534] 1.805 g (6.5 mmol) TEPS 65 was added to 65 mL of EtOH, the mixture was heated to 85 C. and stirred until it was fully dissolved. Then 2.249 g Ammonium chloride was solved in 25 mL H.sub.2O and added to the solution. Afterwards 0.937 g iron powder was added in three portions with few minutes apart. The solution was stirred at 85 C. for two hours until TEPS 65 could not be detected via TLC any longer. Afterwards the mixture was cooled down to 60 C. and the reaction product was collected by extraction using Dichloromethane. The organic layers were washed with H.sub.2O and brine and were dried over Na.sub.2SO.sub.4. Then Dichloromethane was removed on a rotary evaporator, yielding a brown liquid of 1.25 g (76.9%). .sup.1H NMR (200 MHz, chloroform-d) 7.78-6.65 (m, 6H) 3.84 (s, 3H) 2.92 (s, 3H). .sup.13C NMR (50 MHz, chloroform-d) 162.6, 157.9, 133.1, 129.9, 125.9, 123.8, 116.2, 62.2, 52.1. MS m/z: 249 M.sup.+

    Methyl 4-(butylamino)-5-phenoxy-thiophene-2-carboxylate (TEPS 67)

    [0535] ##STR00222##

    [0536] 1.25 g (5.0 mmol) TEPS 66 were solved in 20 mL dimethylformamide, then 0.453 g K.sub.2CO.sub.3 and 792 l butyl iodide were added and the mixture was stirred for three hours under reflux. Afterwards H.sub.2O was added and the product was collected by extraction with ethyl acetate. The organic layers were dried with Na.sub.2SO.sub.4 and then the solvent was removed on a rotary evaporator. Afterwards the product was purified by column chromatography. (Ethyl acetate/Petroleum ether, 3+7), yielding a yellow solid of 0.702 g (4.6%). .sup.1H NMR (200 MHz, chloroform-d) 7.64-6.76 (m, 6H) 3.82 (s, 3H), 3.10 (t, J=7.0 Hz, 1H) 1.66-1.13 (m, 4H) 0.87 (t, J=7.1 Hz, 3H). .sup.13C NMR (50 MHz, chloroform-d) 129.8, 123.7, 116.2, 52.1, 46.4, 32.1, 20.0, 13.8. MS m/z: 318 M.sup.+

    4-(Butylamino)-5-phenoxy-thiophene-2-carboxylic Acid (TEPS 68)

    [0537] ##STR00223##

    [0538] 1.98 mmol (0.7 g) TEPS 67, 2 mmol (0.218 g) KOH were dissolved in 30 mL EtOH and 10 mL H.sub.2O. The reaction mixture was then heated to reflux for three hours. The solvent was removed under reduced pressure and the residue was diluted in H.sub.2O. Then the solution of NaOH was added to increase the pH value to 10. Hereafter the aqueous layer was washed with ethyl acetate and acidified with concentrated HCl. Then the product was extracted with ethyl acetate, washed with water, dried over Na.sub.2SO.sub.4 and then removed under reduced pressure. Afterwards the product was purified by column chromatography. (Ethyl acetate/Petroleum ether, 3+7 10% CH.sub.3COOH)) with a yield of 0.045 g (7.5%). .sup.1H NMR (200 MHz, chloroform-d) 8.20 (s, 1H) 7.56-6.95 (m, 6H) 3.13 (t, J=6.9 Hz, 1H) 1.42 (m, 4H) 0.90 (t, J=7.1 Hz, 3H). 13C NMR (50 MHz, chloroform-d) 167.5, 157.9, 136.5, 129.9, 125.0, 124.0, 116.5, 46.6, 31.9, 20.0, 13.8. MS m/z: 291 M.sup.+

    5-Chloro-4-nitro-thiophene-2-sulfonyl Chloride (TEPS 69) (Yang, J. Et al, 2015)

    [0539] ##STR00224##

    [0540] In a three-neck flask 6.16 mL (46.1 mmol) 5-chlorothiophene-2-sulfonylchlorid was added drowse to 55.6 mL fuming nitric acid. In the beginning the solution was cooled to provide a temperature beneath 60 C. After three hours of stirring, the reaction was completed and the solution was poured on iced-water. The product was collected by vacuum filtration yielding 11.161 g of yellow crystals (92.4%). .sup.1H NMR (200 MHz, chloroform-d) 8.30 (s, 1H). 13C NMR (50 MHz, chloroform-d) 129.8. MS m/z: 263 M.sup.+

    5-Chloro-4-nitro-thiophene-2-sulfonamide (TEPS 70) (Kunzer, A. R., et al, 2010)

    [0541] ##STR00225##

    [0542] 11.31 g (42.6 mmol) TEPS 69 was added to 44.2 mL NH.sub.40H at 0 C. When the addition was complete, the reaction mixture was stirred at room temperature until the solid dissolved. The clear orange solution was cooled in ice, diluted with H.sub.2O and acidified with conc. HCl to precipitate solid. The product was collected by vacuum filtration yielding 4.566 g of yellow powder (44.1%). .sup.1H NMR (200 MHz, DMSO-d6) 8.14 (s, 1H) 7.97 (s, 2H). 13C NMR (50 MHz, DMSO-d6) 141.7, 124.8. MS m/z: 242 M.sup.+

    N-[(5-Chloro-4-nitro-2-thienyl)sulfonyl]-N,N-dimethyl-formamidine (TEPS 71)

    [0543] ##STR00226##

    [0544] 4.566 g (18.8 mmol) TEPS 70 was solved in 22.5 mL acetonitrile and then 2.8 mL N,N-dimehtylformamide-dimethylacetale were added slowly. The reaction was stirred overnight Then the mixture was extracted with ethyl acetate three times and the organic layer was dried with Na.sub.2SO.sub.4. The solvent was removed under reduced pressure, yielding a yellow product of 1.95 g (35.1%). .sup.1H NMR (200 MHz, DMSO-d6) 8.29 (s, 1H) 8.00 (s, 1H) 3.20 (s, 3H) 2.98 (s, 3H). .sup.13C NMR (50 MHz, DMSO-d.sub.6) 160.6, 124.8, 41.3, 35.4. MS m/z: 297 M.sup.+

    N,N-Dimethyl-N-[(4-nitro-5-phenoxy-2-thienyl)sulfonyl]formamidine (TEPS 72)

    [0545] ##STR00227##

    [0546] 6.6 mmol (1.95 g) TEPS 71 were solved in 17 mL acetonitrile and afterwards 0.55 g phenol and 1.85 g K.sub.2CO.sub.3 were added. The mixture was stirred for four hours, then water was added and extracted with ethyl acetate three times and once with brine. The organic layer was dried over Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure resulting in 0.4 g of brown crystals. The product was purified by column chromatography (Ethyl acetate/Petroleum ether 3+7) yielding 2.2 g of an orange product (92.4%). .sup.1H NMR (200 MHz, DMSO-d6) 8.22 (s, 1H) 7.82 (s, 1H) 7.70-7.37 (m, 5H) 3.16 (s, 3H) 2.92 (s, 3H). .sup.13C NMR (50 MHz, chloroform-d) 159.5, 156.8, 130.8, 128.7, 127.8, 124.7, 119.9, 41.9, 36.0. MS m/z: 378 M+

    N-[(4-Amino-5-phenoxy-2-thienyl)sulfonyl]-N,N-dimethyl-formamidine (TEPS 73)

    [0547] ##STR00228##

    [0548] 2.2 g (6.1 mmol) TEPS 72 was added to 40 mL EtOH, the mixture was heated to 85 C. and stirred until it was fully dissolved. Then 4.4 g ammonium chloride was solved in H.sub.2O and added to the solution. Afterwards 0.61 g iron powder was added in three portions with few minutes apart. The solution was stirred at 85 C. for two hours until TEPS 72 could not be detected via TLC any longer. The mixture was cooled down to 60 C. and the reaction product was collected by extraction using Dichloromethane. The combined organic phases were washed with brine and the organic phase was dried over Na.sub.2SO.sub.4. Then the solvent was removed under reduced pressure. The product was purified by column chromatography (Ethyl aceteate/Petroleum ether 1+1) resulting in a yellow liquid of 0.709 g (36.1%). .sup.1H NMR (200 MHz, DMSO-d6) 8.17 (s, 1H) 7.46-6.92 (m, 6H) 4.86 (s, 2H) 3.16 (s, 3H) 2.94 (s, 3H). .sup.13C NMR (50 MHz, DMSO-d.sub.6) 159.6, 158.0, 135.3, 134.6, 132.2, 129.8, 123.3, 123.0, 115.8, 40.9, 35.2. MS m/z: 325 M.sup.+

    N-[[4-(Butylamino)-5-phenoxy-2-thienyl]sulfonyl]-N,N-dimethyl-formamidine (TEPS 74)

    [0549] ##STR00229##

    [0550] 0.7 g (2.2 mmol) TEPS 73 were solved in 3.9 mL dimethylfomamide, then 0.31 g K.sub.2CO.sub.3 and 531 l Butyl iodide were added and the mixture was stirred for three hours under reflux. Afterwards H.sub.2O was added and the product was collected by extraction with ethyl acetate. The organic layers were dried with Na.sub.2SO.sub.4 and then the solvent was removed on a rotary evaporator. Afterwards the product was purified by column chromatography. (Ethyl acetate/Petroleum ether, 3+7) yielding a yellow solid of 0.101 g (11.8%). .sup.1H NMR (200 MHz, chloroform-d) 8.09 (s, 1H) 7.45-6.99, 6H) 3.20-2.98 (m, 8H) 1.70-1.15 (m, 4H) 0.89 (t, J=7.2 Hz, 1H). .sup.13C NMR (50 MHz, chloroform-d) 159.2, 158.0, 131.7, 129.8, 123.9, 121.4, 116.3, 60.4, 46.8, 41.6, 35.7, 31.7, 19.9, 13.8. MS m/z: 381 M.sup.+

    Methyl 1-butyl-7-[(E)-dimethylaminomethyleneamino]sulfonyl-2-propyl-benzimidazole-5-carboxylate (TEPS 77)

    [0551] ##STR00230##

    [0552] 0.5 mmol (193 mg) of TEPS 31 was added to 7.5 mL of ethanol and 1.5 mL of dioxane and this mixture was heated to 85 C. and stirred until it was fully dissolved. Then 0.5 mmol ethyl acetate (25 l), 0.5 mmol conc. acetic acid (14 l) and 5 mmol of ammonium chloride (267.5 mg) in 3 mL water were added. 2 mmol of Iron powder (111.5 mg) were added in three portions 2 minutes apart. The reaction was stirred at 85 C. for another 2.5 hours until BUM131 could not be detected via TLC anymore. The mixture was cooled and then extracted three times with dichloromethane. The combined organic layers were washed with water and brine and dried over Na.sub.2SO.sub.4. The crude product was purified by column chromatography (ethyl acetate/petroleum ether 8+2) to yield 43 mg of yellow solid (21.1% yield). .sup.1H NMR (200 MHz, chloroform-d) 8.55 (s, 2H), 8.15 (s, 1H), 4.95-4.65 (m, 2H), 3.94 (s, 3H), 3.16 (s, 3H), 3.07 (s, 3H), 2.99-2.85 (m, 2H), 2.15-1.90 (m, 2H), 1.90-1.71 (m, 2H), 1.61-1.37 (m, 2H), 1.26 (s, 1H), 1.12 (t, J=7.4 Hz, 3H), 0.99 (t, J=7.3 Hz, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3) 166.6, 159.7, 159.2, 144.3, 133.3, 126.7, 125.1, 124.2, 122.9, 52.4, 45.8, 41.8, 35.8, 33.3, 29.8, 21.1, 20.1, 14.2, 13.9. MS m/z: 408 M.sup.+

    Methyl (2R)-8-[(E)-dimethylaminomethyleneamino]sulfonyl-2-methyl-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylate (TEPS78)

    [0553] ##STR00231##

    [0554] 2 mmol (833 mg) of TEPS 57 were solved in 15 mL ethanol. 2 mL of dioxane were added and the mixture was heated to 85 C. and stirred until it was fully dissolved. Then a solution of 24 mmol of ammonium chloride (1284 mg) in 6 mL water was added. 14 mmol of Iron powder (781 mg) was added in four portions 5 minutes apart. The mixture was cooled to 60 C. and then extracted three times with 25 mL of dichloromethane. The combined organic layers were washed with water and brine and dried over sodium sulfate. The filtrate was evaporated under reduced pressure and the resulting crude product was purified by column chromatography (with ethyl acetate/petroleum ether 7+3 and ethyl acetate only) yielding 1.49 mmol (530 mg) of yellow crystals (74.7% yield).

    [0555] [].sub.D.sup.20=14.159 (c=0.5; Methanol)

    [0556] .sup.1H NMR (200 MHz, DMSO-d.sub.6) 10.70 (s, 1H), 8.29 (s, 1H), 7.88 (d, J=1.9 Hz, 1H), 7.47 (s, 1H), 6.64 (s, 1H), 4.19 (dd, J=6.8, 2.3 Hz, 1H), 3.80 (s, 3H), 3.56 (s, 1H), 3.13 (s, 3H), 2.91 (s, 3H), 1.25 (d, J=6.8 Hz, 3H). .sup.13C NMR (50 MHz, DMSO) 166.8, 165.2, 159.4, 134.6, 126.8, 124.2, 123.3, 117.7, 117.0, 66.4, 51.9, 50.9, 40.9, 35.1, 19.5. MS m/z: 354 M.sup.+

    Methyl (2R)-4-butyl-8-[(E)-dimethylaminomethyleneamino]sulfonyl-2-methyl-3-oxo-1,2-dihydroquinoxaline-6-carboxylate (TEPS 79)

    [0557] ##STR00232##

    [0558] 1 mmol (354 mg) of TEPS 78 were dissolved in 9 mL of N,N-dimethylformamide. 2 mmol (276 mg) of potassium carbonate and 6 mmol (687 L) butyl iodide was added to the mixture and stirred at 90C for 16 hours. After the reaction was completed, the mixture was washed with water and extracted three times with ethyl acetate.

    [0559] The combined organic phases were washed with brine. The organic phase was dried over sodium sulfate and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate) and evaporated under reduced pressure yielding 0.34 mmol (139 mg) of yellow crystals (33.9% yield).

    [0560] [].sub.D.sup.20=11.163 (c=0.5; Methanol)

    [0561] .sup.1H NMR (200 MHz, chloroform-d) 8.37-8.02 (m, 2H), 7.66 (s, 1H), 6.62 (s, 1H), 4.19 (dd, J=6.7, 1.9 Hz, 1H), 4.07-3.76 (m, 5H), 3.15 (s, 3H), 3.03 (s, 3H), 1.67 (s, 2H), 1.74-1.57 (m, 1H), 1.56-1.31 (m, 5H), 0.97 (t, J=6.9 Hz, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3) 166.3, 166.1, 158.9, 137.6, 128.2, 124.7, 124.5, 118.8, 118.3, 52.1, 51.4, 42.1, 41.6, 35.7, 28.9, 20.1, 19.1, 13.8. MS m/z: 410 M.sup.+

    (2R)-4-Butyl-2-methyl-3-oxo-8-sulfamoyl-1,2-dihydroquinoxaline-6-carboxylic Acid (TEPS 80)

    [0562] ##STR00233##

    [0563] 0.48 mmol (200 mg) of TEPS 79 were dissolved in 1.5 mL methanol and 1.5 mL 2N sodium hydroxide and the mixture was stirred at 40 C for 2 hours. After the reaction was completed and the mixture was cooled down to room temperature methanol was evaporated under reduced pressure. Upon adding 1.5 mL 2N hydrochloric acid a light-yellow precipitate was formed. The precipitate was filtered and dried under reduced pressure yielding 0.43 mmol (150 mg) of light-yellow powder (91.5% yield)

    [0564] [].sub.D.sup.20=38.303 (c=0.5; Methanol)

    [0565] .sup.1H NMR (200 MHz, DMSO-d.sub.6) 12.89 (s, 1H), 8.02 (s, 1H), 7.70 (s, 2H), 7.60 (s, 1H), 6.64 (s, 1H), 4.31-4.07 (m, 1H), 3.95 (t, J=7.3 Hz, 2H), 1.65-1.44 (m, 2H), 1.43-1.10 (m, 5H), 0.91 (t, J=7.1 Hz, 3H).

    [0566] .sup.13C NMR (50 MHz, DMSO) 166.8, 166.6, 136.8, 128.2, 126.4, 124.8, 119.2, 118.3, 51.1, 41.2, 28.9, 19.9, 18.8, 14.1.

    [0567] MS m/z: EI not possible

    Methyl (2S)-4-butyl-8-[(E)-dimethylaminomethyleneamino]sulfonyl-2-methyl-3-oxo-1,2-dihydroquinoxaline-6-carboxylate (TEPS 81)

    [0568] ##STR00234##

    [0569] 1 mmol (354 mg) of TEPS58 were dissolved in 9 mL of N,N-dimethylformamide. 2 mmol (276 mg) of potassium carbonate and 6 mmol (687 L) butyl iodide was added to the mixture and stirred at 90 C for 16 hours. After the reaction was completed, the mixture was washed with water and extracted three times with ethyl acetate. The combined organic phases were washed with brine. The organic phase was dried over sodium sulfate and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by column chromatography (ethyl acetate) and evaporated under reduced pressure yielding 0.32 mmol 131 mg of yellow crystals (31.9% yield).

    [0570] [].sub.D.sup.20=+12.083 (c=0.5; Methanol)

    [0571] .sup.1H NMR (200 MHz, DMSO-d.sub.6) 8.29 (s, 1H), 7.97 (d, J=1.7 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 6.76 (s, 1H), 4.26 (dd, J=6.8, 1.9 Hz, 1H), 4.09-3.85 (m, 2H), 3.83 (s, 3H), 3.14 (s, 3H), 2.91 (s, 3H), 1.63-1.44 (m, 2H), 1.38-1.08 (m, 6H), 0.91 (t, J=7.1 Hz, 3H). .sup.1C NMR (50 MHz, DMSO) 166.0, 165.3, 159.4, 136.4, 127.6, 125.1, 123.5, 117.5, 117.3, 52.1, 50.8, 40.9, 35.1, 28.4, 19.4, 19.0, 13.6. MS m/z: 410 M.sup.+

    (2S)-4-Butyl-2-methyl-3-oxo-8-sulfamoyl-1,2-dihydroquinoxaline-6-carboxylic acid (TEPS 82)

    [0572] ##STR00235##

    [0573] 0.12 mmol (50 mg) of TEPS 81 were dissolved in 1.5 mL methanol and 1.5 mL 2N sodium hydroxide and the mixture was stirred at 40 C for 2 hours.

    [0574] After the reaction was completed and the mixture was cooled down to room temperature methanol was evaporated under reduced pressure.

    [0575] Upon adding 1.5 mL 2N hydrochloric acid a light-yellow precipitate was formed. The precipitate was filtered and dried under reduced pressure yielding 0.117 mmol (40 mg) of light-yellow powder (97.5% yield)

    [0576] [].sub.D.sup.20=+35.405 (c=0.5; Methanol)

    [0577] .sup.1H NMR (200 MHz, DMSO-d.sub.6) 12.90 (s, 1H), 8.06-7.96 (m, 1H), 7.71 (s, 1H), 7.60 (s, 1H), 6.65 (s, 1H), 4.30-4.07 (m, 1H), 3.95 (t, J=7.2 Hz, 2H), 1.65-1.42 (m, 2H), 1.30 (d, J=6.7 Hz, 5H), 0.90 (t, J=7.1 Hz, 3H). 13C NMR (50 MHz, DMSO) 166.3, 166.2, 136.4, 127.7, 125.9, 124.4, 118.7, 117.8, 50.7, 40.9, 28.4, 19.4, 18.3, 13.6. MS m/z: not possible EI

    3-(Butylamino)-2-phenoxy-5-(2,2,2-trifluoroethoxymethyl)benzenesulfonamide (TEPS 83)

    [0578] ##STR00236##

    [0579] 84 mg of a dispersion of sodium hydride in mineral oil (2 mmol) was washed two times with dry THF. 3 mL of THF was added to the sodium hydride, then 1.5 mmol (108 l) 2,2,2-Trifluorethanol and 0.5 mmol (184 mg) of TEPS 76 were added. The reaction mixture was stirred at room temperature overnight. After the reaction was completed it was quenched with 3 mL of water. The mixture was then extracted three times with ethyl acetate, the combined organic layers are washed with brine and dried over Na.sub.2SO.sub.4. The organic layers are dried under reduced pressure to yield a white crude product. The crude product was further purified by column chromatography (ethyl acetate/petroleum ether 3+7) and recrystallization from EtOH to yield 78 mg of white powder (36% yield). .sup.1H NMR (200 MHz, DMSO-d.sub.6) 7.40-7.03 (m, 5H), 7.07-6.72 (m, 4H), 4.67 (s, 2H), 4.14 (q, J=9.4 Hz, 2H), 3.03 (t, J=6.9 Hz, 2H), 1.48-1.24 (m, 2H), 1.26-0.98 (m, 2H), 0.77 (t, J=7.2 Hz, 3H). 1C NMR (50 MHz, DMSO-d.sub.6) 156.7, 142.2, 137.3, 135.8, 134.7, 129.0, 124.5 (d, J=279.2 Hz), 121.9, 115.5, 113.9, 113.0, 72.9, 66.6 (q, J=32.8 Hz), 42.0, 30.3, 19.3, 13.6. MS m/z 443

    4-(4-Fluorophenoxy)-3-nitro-5-sulfamoyl-benzoic Acid (TEPS 84) (WO 2012/018635)

    [0580] ##STR00237##

    [0581] To a suspension of 20 mmol (5.61 g) of 4-chloro-3-nitro-5-sulfamoyl-benzoic acid (561 mg) in 30 mL water, 80 mmol NaHCO.sub.3 (6.8 g) were added cautiously followed by 40 mmol (4.77 g) 4-fluorophenol. This solution was stirred at 85 for 16 hours. After cooling to room temperature, the precipitate was filtered off and dissolved in 10 mL of hot water. Then 6N HCl was added and the resulting precipitate was filtered off and dried to yield 4.35 g of a yellow solid (61% yield). .sup.1H NMR (200 MHz, DMSO) 14.01 (brs, 1H), 8.83-8.54 (m, 2H), 7.88 (s, 2H), 7.15 (t, J=8.8 Hz, 2H), 7.05-6.86 (m, 3H). .sup.13C NMR (50 MHz, DMSO) 164.7, 158.56 (d, J=239.5 Hz), 153.25 (d, J=2.3 Hz), 148.2, 143.4, 140.3, 133.6, 130.9, 128.6, 118.24 (d, J=8.5 Hz), 116.56 (d, J=23.7 Hz). MS m/z 356

    3-Amino-4-(4-fluorophenoxy)-5-sulfamoyl-benzoic Acid (TEPS 85)

    [0582] ##STR00238##

    [0583] To an aqueous solution of LiOH (adjusted to pH 11) 10 mmol (3.56 g) TEPS84 and 350 mg palladium on activated charcoal (5% Pd/C) were added. The resulting mixture was hydrogenated at room temperature. When the H.sub.2 uptake became negligible, the mixture was filtered and the filtrate was acidified with 6N HCl and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and dried under reduced pressure to yield 2.15 g of a brown solid (66% yield). .sup.1H NMR (200 MHz, DMSO) 7.78-7.47 (m, 2H), 7.30 (s, 2H), 7.19-7.00 (m, 2H), 6.99-6.76 (m, 2H), 5.32 (s, 2H). .sup.13C NMR (50 MHz, DMSO) 166.9, 157.8 (d, J=236.9 Hz), 152.8 (d, J=2.0 Hz), 143.2, 139.3, 138.3, 128.3, 120.7, 117.3 (d, J=8.4 Hz), 116.1, 115.7. MS m/z 326

    Methyl 3-(benzylamino)-4-(4-fluorophenoxy)-5-sulfamoyl-benzoate (TEPS 86)

    [0584] ##STR00239##

    [0585] To a suspension of 2 mmol (652 mg) TEPS85 in 10 mL MeOH 5 mmol (0.6 mL) benzylbromide were added. The mixture was then refluxed for 16 hour to form a solution. After the reaction was completed, MeOH was removed under reduced pressure and 20 mL 5% NaHCO.sub.3 were added. This mixture was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/petroleum ether 3+7) to yield 351 mg of a white solid (41% yield). .sup.1H NMR (200 MHz, DMSO) 7.67 (d, J=1.9 Hz, 1H), 7.40 (s, 2H), 7.35-7.04 (m, 8H), 6.96-6.80 (m, 2H), 6.21 (t, J=6.0 Hz, 1H), 4.35 (d, J=6.0 Hz, 2H), 3.81 (s, 3H). .sup.13C NMR (50 MHz, DMSO) 165.8, 158.0 (d, J=237.2 Hz), 153.1 (d, J=2.0 Hz), 142.8, 140.5, 139.5, 138.3, 128.8, 127.3, 127.3, 127.1, 117.4 (d, J=8.3 Hz), 116.1, 115.7, 52.9, 46.2. MS m/z 430

    3-(Benzylamino)-2-(4-fluorophenoxy)-5-(hydroxymethyl)benzenesulfonamide (TEPS 87)

    [0586] ##STR00240##

    [0587] In a three necked flask 2 mmol of TEPS86 (860 mg) were dissolved in 8 mL anhydrous THF under argon atmosphere. Then 4 mL of a 1 M DIBAL-H solution in toluene were added. After one, two, three and four hours, respectively, another 2 mL of the 1M DIBAL-H solution in toluene were added each time and the reaction was stirred overnight. After TLC showed no remaining TEPS86 the mixture was cooled to 0 C. and quenched with 5% aqueous NH.sub.4Cl solution causing a gel-like substance to precipitate. The precipitate was then dissolved in 2 N HCl and extracted three times with ethyl acetate. The combined organic layers were washed three times with water, once with brine and dried over Na.sub.2SO.sub.4. The fluids were evaporated under reduced pressure and purified by recrystallization from ethanol to yield 665 mg of beige powder (83% yield). .sup.1H NMR (200 MHz, DMSO) 7.34-7.00 (m, 10H), 6.92-6.74 (m, 3H), 5.86-5.69 (m, 1H), 4.38 (s, 2H), 4.30 (d, J=5.2 Hz, 2H). 13C NMR (50 MHz, DMSO) 157.7 (d, J=236.5 Hz), 153.7, 140.6, 140.0, 137.4, 135.5, 128.7, 128.1, 127.2, 117.2 (d, J=8.1 Hz), 115.7 (d, J=23.3 Hz), 113.5, 112.6, 63.0, 46.3. MS m/z 402

    3-(Benzylamino)-2-(4-fluorophenoxy)-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide (TEPS 88)

    [0588] ##STR00241##

    [0589] 1.5 mmol (604 mg) of TEPS87 were dissolved in 5 mL thionyl chloride and heated to 80 C for three hours. The thionyl chloride was evaporated under reduced pressure. The product was purified by column chromatography (ethyl acetate/petroleum ether 7+3) to yield 470 mg of brown solid (74% yield). 1 mmol (420 mg) of this intermediate benzyl chloride was dissolved in 5 mL of DMF, to this solution 2 mmol (157 l) of 2,2,2-trifluoroethylamine were added and the mixture was stirred at room temperature overnight in a sealed vial. After the reaction was completed, which was verified by thin layer chromatography, the fluid was evaporated under reduced pressure. This crude product was purified by column chromatography (ethyl acetate/petroleum ether 3+7) and recrystallization from ethanol, yielding 86 mg of white crystals (18% yield). .sup.1H NMR (200 MHz, MeOD) 7.32-7.11 (m, 6H), 7.09-6.71 (m, 5H), 4.34 (d, J=3.8 Hz, 2H), 3.84 (d, J=26.0 Hz, 2H), 3.05 (q, J=9.8 Hz, 2H). 13C NMR (50 MHz, MeOD) 142.0, 139.0, 137.3, 128.1, 126.7, 116.5, 116.4, 115.5, 115.4, 115.0, 114.2, 52.1, 46.4. MS m/z 483

    3-(Butylamino)-2-phenoxy-5-(2,2,2-trifluoroethylsulfanylmethyl)benzenesulfonamide (TEPS89)

    [0590] ##STR00242##

    [0591] 84 mg of a dispersion of sodium hydride in mineral oil (2 mmol) was washed two times with dry THF. 3 mL of THF was added to the sodium hydride, then 1 mL 2,2,2-trifluoroethanthiol and 1 mmol (369 mg) of TEPS76 were added and the vial was sealed. The reaction mixture was stirred at room temperature overnight. After the reaction was completed it was quenched with 3 mL of water. The mixture was then extracted three times with ethyl acetate, the combined organic layers are washed with brine and dried over Na.sub.2SO.sub.4. The organic layers were dried under reduced pressure and purified by column chromatography (ethyl acetate/petroleum ether 4+6) and recrystallization from ethanol to yield 257 mg of white powder (57% yield). .sup.1H NMR (200 MHz, CDCl.sub.3) 7.38-7.18 (m, 3H), 7.08 (t, J=7.3 Hz, 1H), 6.99-6.75 (m, 3H), 4.89 (s, 2H), 3.83 (s, 2H), 3.16-2.82 (m, 4H), 1.59-1.28 (m, 2H), 1.31-1.03 (m, 2H), 0.82 (t, J=7.1 Hz, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3) 156.2, 142.5, 136.1, 136.0, 135.1, 130.2, 126.1 (d, J=276.9 Hz), 123.6, 116.3, 115.4, 43.2, 36.8, 33.4 (q, J=32.6 Hz), 31.2, 31.1, 19.9, 13.8. MS m/z 448

    3-(Butylamino)-2-phenoxy-5-(2,2,2-trifluoroethylsulfinylmethyl)benzenesulfonamide (TEPS 90)

    [0592] ##STR00243##

    [0593] To a stirred solution of 0.5 mmol TEPS89 (224 mg) in 5 mL acetonitril was added a solution of 0.35 mmol Oxone (53 mg) in 2 mL water. The reaction was stirred at room temperature for two days until no TLC showed no remaining TEPS89 and then poured into 10 mL of ice water. The solid was filtered and recrystallized from ethanol to yield 162 mg of white powder (70% yield). .sup.1H NMR (200 MHz, DMSO) 7.39-7.12 (m, 4H), 7.11-6.75 (m, 5H), 4.91 (t, J=5.8 Hz, 1H), 4.28 (q, J=12.8 Hz, 2H), 4.14-3.75 (m, 2H), 3.03 (q, J=6.5 Hz, 2H), 1.50-1.22 (m, 2H), 1.24-0.95 (m, 2H), 0.77 (t, J=7.2 Hz, 3H). .sup.13C NMR (50 MHz, DMSO) 156.6, 142.3, 137.4, 136.2, 129.0, 128.3, 127.6, 122.0, 116.5, 115.5, 115.5, 57.4, 53.3 (d, J=26.9 Hz), 42.1, 30.2, 19.3, 13.6. MS m/z 464

    3-(2,2,2-Trifluoroethylsulfanylmethyl)benzenesulfonamide (TEPS 91)

    [0594] ##STR00244##

    [0595] 84 mg of a dispersion of sodium hydride in mineral oil (2 mmol) was washed two times with dry THF. 3 mL of THF was added to the sodium hydride, then 1 mL 2,2,2-trifluoroethanthiol and 1 mmol (250 mg) of 3-bromomethyl-benzenesulfonamide were added. The reaction mixture was stirred at room temperature overnight. After the reaction was completed it was quenched with 3 mL of water. The mixture was then extracted three times with ethyl acetate, the combined organic layers are washed with brine and dried over Na.sub.2SO.sub.4. The organic layers are dried under reduced pressure to yield a white crude product. The crude product was further purified by column chromatography (ethyl acetate/petroleum ether 1+1) and recrystallization from EtOH to yield 135 mg of white powder (61% yield). .sup.1H NMR (200 MHz, MeOD) 7.90 (s, 1H), 7.90-7.75 (m, 1H), 7.65-7.41 (m, 2H), 3.97 (s, 2H), 3.16 (q, J=10.2 Hz, 2H). .sup.13C NMR (50 MHz, MeOD) 145.5, 139.9, 133.8, 130.4, 127.7 (d, J=275.4 Hz), 127.6, 126.2, 37.2, 33.85 (q, J=32.7 Hz). MS m/z 285

    3-(Butylamino)-2-phenoxy-5-(3,3,3-trifluoropropylsulfanylmethyl)benzenesulfonamide (TEPS 92)

    [0596] ##STR00245##

    [0597] 84 mg of a dispersion of sodium hydride in mineral oil (2 mmol) was washed two times with dry THF. 3 mL of THF was added to the sodium hydride, then 1 mL 2,2,2-trifluoropropanthiol and 1 mmol (369 mg) of TEPS76 were added and the vial was sealed. The reaction mixture was stirred at room temperature for two days. After the reaction was completed it was quenched with 3 mL of water. The mixture was then extracted three times with ethyl acetate, the combined organic layers are washed with brine and dried over Na.sub.2SO.sub.4. The organic layers were dried under reduced pressure and purified by column chromatography (ethyl acetate/petroleum ether 4+6) and recrystallization from ethanol to yield 137 mg of white powder (30% yield). .sup.1H NMR (200 MHz, CDCl.sub.3) 7.44-7.18 (m, 3H), 7.08 (t, J=7.3 Hz, 1H), 6.98-6.80 (m, 3H), 4.89 (s, 2H), 3.73 (s, 2H), 3.05 (t, J=6.9 Hz, 2H), 2.74-2.50 (m, 2H), 2.51-2.17 (m, 2H), 1.54-1.30 (m, 2H), 1.31-1.01 (m, 2H), 0.82 (t, J=7.2 Hz, 3H). .sup.13C NMR (50 MHz, MeOD) 156.2, 142.4, 136.2, 135.9, 135.8, 134.3, 130.1, 126.1 (d, J=277.2 Hz), 123.6, 117.4, 116.0, 115.3, 115.2, 43.2, 36.5, 34.6 (q, J=28.7 Hz), 31.1, 23.8 (q, J=3.3 Hz), 19.9, 13.8. MS m/z 462

    3-(Butylamino)-5-[[2-(dimethylamino)-ethylamino]-methyl]-2-phenoxy-benzenesulfonamide Hydrochloride (TEPS 93)

    [0598] ##STR00246##

    [0599] 2 mmol (740 mg) of TEPS76 were dissolved in a solution consisting of 5 mL DMF and 1 mL TEA. To this 2 mmol (440 L) of N,N-dimethylethylendiamine 98% were added and the mixture was stirred at room temperature overnight. After the reaction was accomplished, it was purified through column chromatography (ethyl acetate/triethylamine/EtOH 6+3+1). The crude product was dissolved in dry THF and 1 mL of a hydrogen chloride solution 1.0 M in diethyl ether was added. The resulting precipitate was filtered off to yield 123 mg of yellow powder (13% yield). .sup.1H NMR (200 MHz, MeOD) 7.42 (d, J=2.0 Hz, 1H), 7.37-7.18 (m, 3H), 7.05 (t, J=7.3 Hz, 1H), 6.91 (d, J=7.6 Hz, 2H), 4.40-4.23 (m, 2H), 3.65 (d, J=10.5 Hz, 4H), 3.15 (t, J=6.8 Hz, 2H), 3.00 (s, 6H), 1.57-1.27 (m, 2H), 1.30-1.00 (m, 2H), 0.81 (t, J=7.2 Hz, 3H). .sup.13C NMR (50 MHz, MeOD) 156.6, 142.7, 137.9, 137.4, 129.2, 128.7, 122.6, 116.7, 115.8, 115.2, 52.9, 51.2, 42.7, 42.6, 41.9, 30.5, 19.5, 12.6. MS EI not possible

    5-(1,3-Benzothiazolyl-2-sulfanylmethyl)-3-(butylamino)-2-phenoxy-benzenesulfonamide (TEPS 93)

    [0600] ##STR00247##

    [0601] 1 mmol (368 mg) of TEPS76 was dissolved in a solution consisting of 3 mL DMF and 1 mL TEA. Thereafter, 2 mmol (338 mg) 2-mercaptobenzothiazole were added and the mixture was stirred at room temperature overnight. After the reaction was accomplished, it was purified through column chromatography (ethyl acetate/petroleum ether 3+7). The crude product was then purified by recrystallization from EtOH to yield 140 mg of white crystal (28% yield). .sup.1H NMR (200 MHz, DMSO) 8.01 (d, J=7.8 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.54-7.32 (m, 2H), 7.30-7.07 (m, 6H), 6.97 (t, J=7.3 Hz, 1H), 6.88-6.62 (m, 2H), 4.83 (t, J=5.9 Hz, 1H), 4.67 (s, 2H), 3.10-2.79 (m, 2H), 1.41-1.15 (m, 2H), 1.13-0.87 (m, 2H), 0.68 (t, J=7.1 Hz, 3H). .sup.13C NMR (50 MHz, DMSO) 166.5, 157.1, 153.0, 142.6, 137.8, 136.0, 136.0, 135.2, 135.0, 129.5, 126.9, 125.1, 122.4, 122.3, 121.6, 115.9, 114.7, 42.5, 36.9, 30.7, 19.7, 14.0. MS m/z 499

    3-(Butylamino)-2-phenoxy-5-(2-pyridylsulfanylmethyl)benzenesulfonamide (TEPS 95)

    [0602] ##STR00248##

    [0603] To 3 mL DMF and 2 mL triethylamine 1 mmol (369 mg) TEPS76 and 1 mmol (114 mg) 2-mercaptopyridine were added and stirred overnight at room temperature. After the reaction was completed DMF was evaporated and water was added. The mixture was extracted three times with ethyl acetate, washed three times with water and once with brine. It was purified by column chromatography (ethyl acetate/petroleum ether 4+6). After that the product was recrystallized from 70% isopropanol yielding 221 mg of light yellow crystals. .sup.1H NMR (200 MHz, chloroform-d) 8.46 (d, J=3.4 Hz, 1H), 7.59-7.41 (m, 1H), 7.39-7.13 (m, 4H), 7.13-6.83 (m, 5H), 4.87 (s, 2H), 4.43 (s, 2H), 3.00 (t, J=6.9 Hz, 2H), 1.45-1.25 (m, 2H), 1.24-1.03 (m, 2H), 0.80 (t, J=7.2 Hz, 3H). .sup.13C NMR (50 MHz, chloroform-d) 158.1, 156.2, 149.4, 142.1, 136.8, 136.2, 135.5, 129.9, 123.3, 122.3, 119.9, 116.5, 115.4, 115.2, 100.0, 100.0, 43.0, 34.0, 31.0, 19.8, 13.7. MS m/z 444

    3-(Butylamino)-5-(1H-imidazol-2-ylsulfanylmethyl)-2-phenoxy-benzenesulfonamide (TEPS96)

    [0604] ##STR00249##

    [0605] 1 mmol (369 mg) of 3-(butylamino)-5-(chloromethyl)-2-phenoxy-benzenesulfonamide (TEPS 76) was dissolved in 3 mL DMF and 1 mL TEA. To this 2 mmol (205 mg) of 2-mercaptoimidazole were added and the mixture was stirred at room temperature overnight. After the reaction was accomplished, which was verified by the thin layer chromatography, it was purified through column chromatography with the mobile phase consisting of ethyl acetate and petroleum ether (9+1). Those fractions which contained the sample were united and the mobile phase was evaporated under reduced pressure, yielding 308 mg of white brown powder (71% yield). .sup.1H NMR (200 MHz, MeOD) 7.35-7.17 (m, 2H), 7.14-6.93 (m, 4H), 6.93-6.77 (m, 2H), 6.62-6.59 (m, 1H), 4.14 (s, 1H), 2.94 (t, J=6.7 Hz, 2H), 1.46-1.22 (m, 2H), 1.23-0.98 (m, 2H), 0.80 (t, J=7.1 Hz, 3H). .sup.13C NMR (50 MHz, MeOD) 156.8, 142.2, 138.4, 136.5, 136.0, 135.8, 129.1, 122.3, 115.3, 115.1, 114.4, 42.3, 39.1, 30.6, 19.5, 12.6. MS m/z 432

    3-(Butylamino)-2-phenoxy-5-[(2-pyridylamino)methyl]benzenesulfonamide (TEPS 97)

    [0606] ##STR00250##

    [0607] 1 mmol (348 mg) of 3-(butylamino)-5-formyl-2-phenoxy-benzenesulfonamide was dissolved in 10 mL 1,2-dichlorethane and 1 mmol (29 L) of acetic acid and 1.2 mmol 2-aminopyridine were added. After stirring the mixture for two hours, 1.5 mmol of triacetoxyborohydride (NaBH(OAc).sub.3) were added and the mixture was stirred overnight. The product was diluted with 40 mL of dichloromethane and 10 mL saturated NaHCO.sub.3. After washing it with brine it was evaporated under reduced pressure. The purification was made by column chromatography (ethyl acetate/petroleum ether 6+4) and recrystallization out of 70% EtOH, resulting in 130 mg of white crystals (30% yield). .sup.1H NMR (200 MHz, DMSO) 8.06-7.88 (m, 1H), 7.51-6.30 (m, 12H), 4.76-4.61 (m, 1H), 4.55-4.41 (m, 2H), 3.13-2.87 (m, 2H), 1.40-1.20 (m, 2H), 1.19-0.97 (m, 2H), 0.74 (t, J=7.0 Hz, 3H). .sup.13C NMR (50 MHz, DMSO) 159.0, 157.3, 147.9, 142.4, 138.9, 137.3, 137.3, 135.2, 129.5, 122.4, 115.9, 114.2, 112.8, 112.4, 108.6, 44.4, 42.6, 30.8, 19.8, 14.1. MS m/z 427

    3-(Butylamino)-N-(4-fluorophenyl)-4-phenoxy-5-sulfamoyl-benzamide (TEPS 98)

    [0608] ##STR00251##

    [0609] 1 mmol (364 mg) of bumetanide was dissolved in 5 mL THF, then 1.2 mmol (194 mg) 1,1-carbonyldiimidazole were added and the mixture was stirred for three hours. Afterwards 2 mmol (222 mg) 4-Fluoroaniline were added and the mixture was stirred at room temperature overnight. After the reaction was completed, 20 mL of 5% sodium bicarbonate solution were added and the reaction was extracted three times with ethyl acetate. The collected organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified via recrystallization using EtOH to yield 200 mg yellow powder (44% yield). .sup.1H NMR (200 MHz, DMSO) 10.40 (s, 1H), 7.86-7.69 (m, 2H), 7.68 (d, J=1.9 Hz, 1H), 7.45 (d, J=1.9 Hz, 1H), 7.41-7.10 (m, 6H), 7.02 (t, J=7.3 Hz, 1H), 6.96-6.77 (m, 2H), 4.97 (t, J=5.6 Hz, 1H), 3.12 (q, J=6.5 Hz, 2H), 1.49-1.28 (m, 2H), 1.23-0.97 (m, 2H), 0.78 (t, J=7.2 Hz, 3H). .sup.13C NMR (50 MHz, DMSO) 164.7, 158.41 (d, J=240.4 Hz) 156.4, 142.2, 138.5, 137.5, 135.32 (d, J=2.5 Hz), 132.2, 129.1, 122.54 (d, J=7.9 Hz), 122.2, 115.6, 115.19 (d, J=22.2 Hz), 113.6, 42.1, 30.3, 19.3, 13.6. MS m/z 347

    3-(Butylamino)-5-[(4-fluoroanilino)methyl]-2-phenoxy-benzenesulfonamide (TEPS 99)

    [0610] ##STR00252##

    [0611] 0.33 mmol (150 mg) of TEPS98 was dissolved in 20 mL tetrahydrofuran. 1.32 mmol (4 equivalent, 100 mg) of borane dimethyl sulfide complex were added. The mixture was stirred at 86 C. overnight under reflux. After TLC showed that no starting material was present, the mixture was cooled down to room temperature and quenched with 20 mL of half-saturated aqueous amount of NaHCO.sub.3. Afterwards the mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by recrystallization using EtOH. Yield: 56 mg (38%).sup.1H NMR (200 MHz, DMSO) 7.25 (t, J=7.7 Hz, 2H), 7.15-7.04 (m, 3H), 7.06-6.76 (m, 6H), 6.67-6.50 (m, 2H), 6.24 (t, J=6.0 Hz, 1H), 4.72 (t, J=5.7 Hz, 1H), 4.24 (d, J=5.9 Hz, 2H), 2.99 (q, J=6.2 Hz, 2H), 1.40-1.18 (m, 2H), 1.21-0.93 (m, 2H), 0.74 (t, J=7.1 Hz, 3H). .sup.13C NMR (50 MHz, DMSO) 156.8, 154.32 (d, J=241.5 Hz), 145.3 145.29 (d, J=1.4 Hz), 137.9, 137.1, 134.9, 129.0, 121.8, 115.5, 115.20 (d, J=21.9 Hz), 113.5, 112.98 (d, J=7.3 Hz), 112.4, 46.8, 42.1, 39.5, 30.3, 19.3, 13.6. MS m/z 333

    N-(2,7-Dihydro-1H-benzimidazol-2-yl)-3-(butylamino)-4-phenoxy-5-sulfamoyl-benzamide (TEPS 100)

    [0612] ##STR00253##

    [0613] 2 mmol (728 mg) of bumetanide was dissolved in in 5 mL dry tetrahydrofuran. 2.4 mmol (388 mg) 1,1-carbonyldiimidazole were added and the mixture was stirred for two hours. After the thin-layer chromatography showed no remaining bumetanide, 4 mmol (532 mg) trifluoropropan-1-amine were added and the mixture was stirred at room temperature overnight. After the reaction was completed 20 mL of 5% NaHCO.sub.3 were added and it extracted three times with ethyl acetate. The collected organic phase was washed with brine and dried over Na.sub.2SO.sub.4. The solvent was then removed under reduced pressure. The crude product was purified via recrystallization from MeOH. Yield: 413 mg (43%). .sup.1H NMR (200 MHz, DMSO) 12.38 (brs, 1H), 7.95 (d, J=1.7 Hz, 1H), 7.74 (d, J=1.7 Hz, 1H), 7.50-7.40 (m, 2H), 7.35-7.22 (m, 4H), 7.20-7.13 (m, 2H), 7.01 (t, J=7.3 Hz, 1H), 6.88 (d, J=7.8 Hz, 2H), 4.90 (t, J=5.5 Hz, 1H), 3.13 (q, J=6.4 Hz, 2H), 1.41 (p, J=6.9 Hz, 2H), 1.25-1.04 (m, 2H), 0.79 (t, J=7.2 Hz, 3H). .sup.13C NMR (50 MHz, DMSO) 156.5, 142.1, 138.8, 137.4, 129.2, 122.3, 121.9, 115.6, 114.8, 114.3, 42.2, 30.4, 19.4, 13.7. MS m/z 481

    3-(Butylamino)-4-phenoxy-5-sulfamoyl-N-(3,3,3-trifluoropropyl)benzamide (TEPS 101)

    [0614] ##STR00254##

    [0615] 1 mmol (364 mg) of bumetanide was dissolved in in 5 mL dry tetrahydrofuran. 1.2 mmol (194 mg) 1,1-carbonyldiimidazole were added and the mixture was stirred for three hours. After the thin-layer chromatography showed that all bumetanide reacted, 2 mmol (300 mg) trifluoropropan-1-Amine were added and the mixture was stirred at room temperature overnight. After the reaction was completed 20 mL of 5% NaHCO.sub.3 were added and it was extracted three times with ethyl acetate. The collected organic phase was washed with brine and dried over Na.sub.2SO.sub.4. The solvent was then removed under reduced pressure. The crude product was purified via recrystallization from EtOH. Yield: 220 mg (47%).

    [0616] .sup.1H NMR (200 MHz, MeOD) 7.74-7.61 (m, 2H), 7.40 (d, J=2.0 Hz, 1H), 7.29 (t, J=7.9 Hz, 2H), 7.10-7.03 (m, 2H), 6.96-6.85 (m, 2H), 3.64 (t, J=7.0 Hz, 2H), 3.12 (t, J=6.8 Hz, 2H), 2.70-2.37 (m, 2H), 1.42 (p, J=6.8 Hz, 2H), 1.24-1.05 (m, 2H), 0.81 (t, 3H). .sup.13C NMR (50 MHz, MeOD) 169.1, 157.8, 144.0, 140.6, 138.4, 132.9, 130.7, 127.96 (d, J=276.2 Hz), 124.0, 116.6, 114.9, 114.5, 43.7, 34.60 (q, J=4.0 Hz), 34.03 (q, J=27.8 Hz), 32.0, 20.8, 14.0. MS m/z 459

    3-(Butylamino)-2-phenoxy-5-[(3,3,3-trifluoropropylamino)methyl]benzenesulfonamide (TEPS102)

    [0617] ##STR00255##

    [0618] 1.56 mmol (363 mg) of TEPS101 was dissolved in 20 mL of THF and 5.8 mmol (0.556 mL) borane dimethylsulfid complex was added. The reaction mixture was then stirred at 86 overnight. Once TLC showed that no starting material was present, the mixture was cooled to room temperature and then quenched with 20 mL of half-saturated aqueous NaHCO.sub.3. It was extracted three times with 25 mL of ethyl acetate, washed brine and dried over Na.sub.2SO.sub.4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (ethyl acetate/petroleum ether and TEA, 1:1+20 mL of TEA) and recrystallized from 70% EtOH to yield 178 mg. (Yield 26%). .sup.1H NMR (200 MHz, CDCl.sub.3) 7.38-7.16 (m, 3H), 7.06 (t, J=7.3 Hz, 1H), 6.91 (d, J=7.3 Hz, 3H), 4.90 (s, 1H), 3.79 (s, 2H), 3.06 (q, J=6.7 Hz, 2H), 2.91 (t, J=7.1 Hz, 2H), 2.34 (qt, J=10.9, 7.1 Hz, 2H), 1.41 (p, J=6.8 Hz, 2H), 1.17 (dq, J=13.7, 6.9 Hz, 2H), 0.82 (t, J=7.2 Hz, 3H). .sup.13C NMR (50 MHz, CDCl.sub.3) 156.4, 142.4, 138.2, 135.7, 135.6, 133.0, 130.1, 126.79 (d, J=276.8 Hz), 123.5, 120.5, 115.5, 115.3, 114.3, 53.4, 43.2, 42.23 (q, J=3.3 Hz), 34.41 (q, J=27.7 Hz), 31.2, 19.9, 13.8. MS m/z 445

    3-(Butylamino)-N-(2-morpholinoethyl)-4-phenoxy-5-sulfamoyl-benzamide (TEPS 103)

    [0619] ##STR00256##

    [0620] To a solution of 1 mmol (364 mg) of bumetanide in 5 mL dry THF, 1.2 mmol (194 mg) of 1,1-carbonyldiimidazole (CDI) were added and the mixture was stirred for 3 hours. Once TLC showed that all the bumetanide reacted, 2 mmol (0.262 mL) of 4-(2aminoethyl)morpholin were added and the mixture was stirred at room temperature overnight. After the reaction was completed, 20 mL of 5% NaHCO.sub.3 were added and it was extracted with 25 mL ethyl acetate three times. The organic Phase was washed brine and then dried over Na.sub.2SO.sub.4. The solvent was removed under reduced pressure. The crude product was purified via flash column chromatography (TEA/ethyl acetate, 1:9). The obtained substance was dried under vacuum to yield 385 mg of white powder (80% yield). .sup.1H NMR (200 MHz, MeOD) 7.69 (d, J=2.0 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.29 (t, J=7.9 Hz, 2H), 7.09-7.00 (m, 2H), 6.96-6.87 (m, 2H), 3.76-3.67 (m, 4H), 3.56 (t, J=6.6 Hz, 2H), 3.13 (t, J=6.8 Hz, 2H), 2.67-2.50 (m, 6H), 1.43 (p, J=6.9 Hz, 2H), 1.28-1.09 (m, 2H), 0.82 (t, J=7.2 Hz, 3H). .sup.13C NMR (50 MHz, MeOD) 169.0, 157.8, 143.9, 140.4, 138.3, 130.6, 124.0, 116.6, 115.0, 114.5, 67.7, 58.6, 54.7, 43.7, 37.8, 32.0, 20.8, 14.0. MS m/z 476

    3-(Butylamino)-4-phenoxy-N-[2-(1-piperidyl)ethyl]-5-sulfamoyl-benzamide (TEPS 104)

    [0621] ##STR00257##

    [0622] To a solution of 1 mmol (364 mg) of bumetanide in 5 mL dry THF, 1.2 mmol (194 mg) of 1,1-carbonyldiimidazole (CDI) were added and the mixture was stirred for 2 hours. Once TLC showed that all the bumetanide reacted, 2 mmol (0.285 mL) of 4-(2aminoethyl)piperidin were added and the mixture was stirred at room temperature overnight. After the reaction was completed, 20 mL of 5% NaHCO.sub.3 were added and it was extracted with 25 mL ethyl acetate three times. The organic Phase was washed with brine and then dried over Na.sub.2SO.sub.4. The solvent was removed under reduced pressure. The crude Product was purified by recrystallization from 70% EtOH to yield 302 mg (Yield 67%). .sup.1H NMR (200 MHz, MeOD) 7.69 (d, J=2.0 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.29 (t, J=7.9 Hz, 2H), 7.05 (t, J=7.3 Hz, 1H), 6.97-6.84 (m, 2H), 3.56 (t, J=6.8 Hz, 2H), 3.13 (t, J=6.8 Hz, 2H), 2.67-2.45 (m, 6H), 1.73-1.33 (m, 8H), 1.26-1.05 (m, 2H), 0.82 (t, J=7.2 Hz, 3H). .sup.13C NMR (50 MHz, MeOD) 169.0, 157.8, 143.9, 140.5, 138.3, 133.3, 130.6, 124.0, 116.6, 115.0, 114.5, 58.9, 55.5, 43.7, 38.0, 32.0, 26.6, 25.1, 20.9, 14.0. MS m/z 474

    3-(Butylamino)-2-phenoxy-5-(3,3,3-trifluoropropoxymethyl) benzenesulfonamide (TEPS 105)

    [0623] ##STR00258##

    [0624] In a three necked round bottom flask 4 mmol (168 mg) of a dispersion of sodium hydride in mineral oil (60%) were washed two times with dry THF. After that 5 mL of THF, 4.5 mmol (0.4 mL) 3,3,3-trifluoro-1-propanol and 1 mmol (368 mg) of TEPS76 were added. The reaction mixture was stirred at room temperature overnight. After the reaction was completed it was quenched with 10 mL water. The mixture was then extracted three times with ethyl acetate, the combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (ethyl acetate/petroleum ether 4+6) and recrystallization from toluene to yield 122 mg of white powder (27% yield). .sup.1H NMR (200 MHz, MeOD) 7.37-7.15 (m, 3H), 7.10-6.81 (m, 4H), 4.55 (s, 2H), 3.76 (t, J=6.3 Hz, 2H), 3.07 (t, J=6.8 Hz, 2H), 2.66-2.37 (m, 2H), 1.53-1.27 (m, 2H), 1.30-1.02 (m, 2H), 0.81 (t, J=7.2 Hz, 3H). .sup.13C NMR (50 MHz, MeOD) 158.2, 143.8, 137.8, 137.5, 130.5, 123.7, 116.5, 115.4, 114.5, 73.5, 64.32 (q, J=3.6 Hz), 43.8, 35.04 (q, J=28.3 Hz), 32.1, 20.9, 14.0. MS m/z 446

    3-[(2,2,2-Trifluoroethylamino)methyl]benzenesulfonamide

    [0625] Error! Objects cannot be created from editing field codes.

    [0626] 5 mmol (1.41 g) of 2,2,2-trifluoro-N-[(4-sulfamoylphenyl)methyl]acetamide (Augurusa, A., et al., 2016) were dissolved in 10 mL dry tetrahydrofuran (THF). The mixture was cooled at 0-4 C. and flooded with argon gas. 25 mmol (12.5 mL) of LiAlH.sub.4 (2.0 M in THF) were added carefully in three portions every 30 minutes, then the solution was heated to 60 C. for 3 hours. The mixture was stirred overnight at room temperature. Again, the mixture was cooled at 0-4 C. and the reaction was quenched with 5% aqueous NH.sub.4Cl. 2 N HCl was added until the mixture was completely clear and extracted two times with ethyl acetate. The aqueous phase was neutralized by adding 2 M NaOH and again extracted two times with ethyl acetate. The second organic phase was dried over sodium sulfate and evaporated under reduced pressure. Afterwards the product was recrystallized from isopropanol. The resulting product yielded 387 mg of white crystals (28.9% yield). .sup.1H NMR (200 MHz, DMSO-d.sub.6) 7.79 (A-part of AB system, J.sub.AB=8.3 Hz, 2H), 7.52 (B-part of AB system, J.sub.AB=8.3 Hz, 2H), 7.31 (s, 2H), 3.86 (d, J=5.7 Hz, 2H), 3.32-3.11 (m, 2H), 3.09-2.96 (m, 1H). .sup.1C NMR (50 MHz, DMSO-d.sub.6) 144.3, 142.6, 126.2 (q, J=279.3 Hz), 128.1, 125.6, 51.8, 48.7 (q, J=30.3 Hz). MS m/z: 269 M.sup.+

    2-(2,2,2-Trifluoroethyl)-3,4-dihydro-1H-isoquinoline-7-sulfonamide

    [0627] Error! Objects cannot be created from editing field codes.

    2-(2,2,2-Trifluoroethyl)-3,4-dihydro-1H-isoquinoline-6-sulfonamide

    [0628] Error! Objects cannot be created from editing field codes.

    Example 2: NKCC1 Inhibitory Activity of the Compounds According to the Invention

    [0629] The compounds of formula (I) according to the present invention are inhibitors of Na.sup.+K.sup.+-2Cl.sup.-cotransporters (NKCCs), particularly of NKCC1. The NKCC1 inhibitory activity of the compounds of the invention can be determined, for example, using the following NKCC1A activity assay.

    [0630] To activate NKCC1A prior to the uptake experiment, hNKCC1A-expressing oocytes (Lykke, K., et al. 2016) or uninjected control oocytes are pre-incubated for 30 min at room temperature in a K.sup.+-free solution. To measure K.sup.+ influx, oocytes are exposed to an isosmotic test solution in which KCl is substituted for choline chloride and .sup.86Rb.sup.+ is added as a tracer for K.sup.+. Bumetanide (positive control), a compound of formula (I) according to the invention (drug), or control vehicle (negative control) are added to the test solution. The uptake assay is then performed at room temperature with mild agitation for 5 min. The influx experiments are terminated and the radioactivity present is determined by liquid scintillation -counting with Opti-Fluor scintillation using a Liquid Scintillation Analyzer. hNKCC1A-mediated K.sup.+ uptake is then assessed as ([flux.sub.NKCC1-expressing oocytes in presence of M drug][flux.sub.uninjected oocytes in presence of M drug]), in order to correct for endogenous NKCC activity. A reduction in hNKCC1A-mediated K.sup.+ uptake observed with a test compound is indicative of the compound inhibiting NKCC1. When the exemplary compounds of formula (I) described in Example 1 are subjected to this assay, it can be confirmed that they exhibit NKCC1 inhibitory activity.

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