US 5,686,442 A · Tricyclic benzazepine and benzothiazepine derivatives

Abstract

The tricyclic benzazepine and benzothiazepine derivatives represented by the formula (I) and pharmacologically acceptable salts thereof are disclosed. ##STR1## wherein Z represents CO, --CR.sup.6 R.sup.7 -- or --S(O).sub.n, R represents hydrogen, alkyl, phenylalkyl, or a protective group of a triazole ring, R.sup.1 -R.sup.5 represent hydrogen, alkyl, alkenyl, alkoxy, amino, oxim or hydroxyl. These compounds have anti-allergic effect and are useful for the treatment and prophylaxis of allergic diseases.

A tricyclic benzazepine or benzothiazepine compound represented by the formula (I):

##STR20## wherein --Z-- represents
carbonyl;
a group --CR.sup.6 R.sup.7 --, wherein R.sup.6 and R.sup.7, which may be the same or different, represent
hydrogen,
hydroxyl,
C.sub.1-12 alkyl optionally substituted by halogen, hydroxyl or C.sub.3-7 cycloalkyl, or
C.sub.1-12 alkoxy optionally substituted by halogen, hydroxyl or C.sub.3-7 cycloalkyl;
a group --(C.dbd.N--OR.sup.8)--, wherein R.sup.8 represents
hydrogen or
C.sub.1-12 alkyl optionally substituted by C.sub.3-7 cycloalkyl, or
a group --S(O).sub.n --, wherein n is an integer of 0-2;
--R represents
hydrogen;
C.sub.1-6 alkyl optionally substituted by halogen, hydroxyl, C.sub.3-7 cycloalkyl or C.sub.1-4 alkoxy;
phenyl C.sub.1-4 alkyl, of which the hydrogen atoms on the benzene ring may be optionally substituted by halogen, hydroxyl, nitro, C.sub.1-4 alkyl or C.sub.1-4 alkoxy;
or
a protective group of the triazole group;
--R.sup.1 represents
hydrogen;
hydroxyl;
C.sub.1-2 alkyl optionally substituted by halogen, hydroxyl or C.sub.3-7 cycloalkyl;
phenyl C.sub.1-4 alkyl, of which the hydrogen atoms on the benzene ring may be optionally substituted by halogen, hydroxyl, nitro, C.sub.1-4 alkyl or C.sub.1-4 alkoxy;
--R.sup.2, R.sup.3, R.sup.4 and R.sup.5, which may be the same or different, represent any one of the following (a)-(v):
(a) hydrogen;
(b) halogen;
(c) hydroxyl which may be protected;
(d) cyano;
(e) nitro;
(f) thiol;
(g) formyl;
(h) C.sub.1-12 alkyl optionally substituted by halogen, hydroxyl or C.sub.3-7 cycloalkyl;
(i) phenyl optionally substituted by C.sub.1-4 alkyl;
(j) phenyl C.sub.1-4 alkyl, of which the hydrogen atoms on the benzene ring may be optionally substituted by halogen, hydroxyl, nitro, amino, sulfonyl, C.sub.1-4 alkyl or C.sub.1-4 alkoxy;
(k) C.sub.2-12 alkenyl, which includes one or more carbon-carbon double bonds and may be optionally substituted by
(1) halogen,
(2) cyano,
(3) C.sub.3-7 cycloalkyl,
(4) phenyl,
(5) a group --COR.sup.9, wherein R.sup.9 represents
hydrogen,
C.sub.1-6 alkyl, or
phenyl optionally substituted by halogen, hydroxyl,
C.sub.1-4 alkyl or C.sub.1-4 alkoxy,
(6) a group --COOR.sup.10, wherein R.sup.10 represents hydrogen or C.sub.1-6 alkyl,
(7) a group --CONR.sup.11 R.sup.12, wherein R.sup.11 and R.sup.12, which may be the same or different, represent
(i) hydrogen,
(ii) C.sub.1-6 alkyl optionally substituted by
hydroxyl;
C.sub.1-4 alkoxy;
amino which may be optionally substituted by C.sub.1-4 alkyl, C.sub.1-16 alkylcarbonyl, benzoyl, .alpha.-naphthoyl, .beta.-naphthoyl or sulfonyl;
phenyl which may be optionally substituted by halogen, hydroxyl, C.sub.1-4 alkyl (which may be optionally substituted by a saturated 5-7 membered heterocyclic ring containing one or two nitrogen atoms, which heterocyclic ring is selected from the group consisting of piperidino, 4-piperidinyl, 1-pyrrolidinyl, piperadinyl and morpholino and which may be optionally substituted by C.sub.1-4 alkyl), C.sub.1-4 alkoxy or carboxyl;
or
a saturated or unsaturated 5-7 membered heterocyclic ring containing one or more of oxygen atoms, nitrogen atoms or sulfur atoms, which heterocyclic ring is selected from the group consisting of pyridine, imidazole, oxazole, thiazole, pyrimidine, furan, thiophene, pyrrole, pyrrolidine, piperidine, tetrahydrofuran, oxazoline, quinoline and isoquinoline and which heterocyclic ring may be optionally substituted by C.sub.1-4 alkyl or phenyl C.sub.1-4 alkyl or may be a bicyclic ring fused with another ring, or
(iii) phenyl, or
(iv) a saturated or unsaturated 5-7 membered heterocyclic ring which is formed by R.sup.11 and R.sup.12 together with the nitrogen atom R.sup.11 and R.sup.12 attached thereto and may further contain one or more of oxygen atoms, nitrogen atoms or sulfur atoms, which heterocyclic ring is selected from the group consisting of tetrazole, thiazole, imidazole, pyridine, pyrimidine and pyrazine and which heterocyclic ring may be optionally substituted by C.sub.1-4 alkyl or phenyl C.sub.1-4 alkyl or may be a bicyclic ring fused with another ring;
(l) C.sub.1-12 alkoxy optionally substituted by
(1) halogen,
(2) hydroxyl,
(3) cyano,
(4) C.sub.3-7 cycloalkyl,
(5) epoxy,
(6) phenyl optionally substituted by halogen, hydroxyl, nitro, C.sub.1-4 alkyl or C.sub.1-4 alkoxy,
(7) C.sub.1-4 alkoxy,
(8) phenoxy optionally substituted by halogen, hydroxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or carboxyl,
(9) amino optionally substituted by C.sub.1-4 alkyl, C.sub.1-6 alkylcarbonyl, benzoyl, .alpha.-naphthoyl, .beta.-naphthoyl or sulfonyl,
(10) a group --COR.sup.13, wherein R.sup.13 represents
hydrogen,
C.sub.1-6 alkyl,
phenyl optionally substituted by halogen, hydroxyl, C.sub.1-4 alkyl or C.sub.1-4 alkoxy, or
phenyl C.sub.1-4 alkyl, of which the hydrogen atoms on the benzene ring may be optionally substituted by halogen, hydroxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or carboxyl,
(11) a group --COOR.sup.14, wherein R.sup.14 represents hydrogen or C.sub.1-6 alkyl,
(12) a group --CONR.sup.15 R.sup.16, wherein R.sup.15 and R.sup.16 may be the same or different and represent
hydrogen,
C.sub.1-6 alkyl optionally substituted by hydroxyl, C.sub.1-4 alkoxy, or amino (which may be optionally substituted by C.sub.1-4 alkyl, C.sub.1-6 alkylcarbonyl, benzoyl, .alpha.-naphthoyl, .beta.-naphthoyl or sulfonyl), or
phenyl, or
(13) a saturated or unsaturated 5-7 membered heterocyclic ring containing one or more of oxygen atoms, nitrogen atoms or sulfur atoms, which heterocyclic ring is selected from the group consisting of piperidino, 4-piperidinyl, 1-pyrrolidinyl, piperazinyl and morpholino and which heterocyclic ring may be optionally substituted by C.sub.1-4 alkyl or phenyl C.sub.1-4 alkyl, or may be a bicyclic ring fused with another ring,
(m) phenoxy optionally substituted by hydroxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or carboxyl;
(n) C.sub.2-12 alkenyloxy optionally substituted by C.sub.1-4 alkyl or phenyl;
(o) C.sub.1-12 alkylthio optionally substituted by hydroxyl, C.sub.3-7 cycloalkyl, C.sub.2-4 alkenyl, C.sub.1-4 alkoxy or benzyl;
(p) a group --C.dbd.N--OR.sup.26, wherein R.sup.26 represents
hydrogen,
C.sub.1-6 alkyl,
phenyl C.sub.1-4 alkyl, or
phenyl;
(q) a group --(CH.sub.2).sub.m OR.sup.17, wherein m is an integer of 1-4, and R.sup.17 represents
hydrogen,
C.sub.1-6 alkyl optionally substituted by halogen, hydroxyl or C.sub.3-7 cycloalkyl,
phenyl C.sub.1-4 alkyl, of which the hydrogen atoms of the benzene ring may be optionally substituted by hydroxyl,
C.sub.1-4 alkyl or C.sub.1-4 alkoxy,
phenyl, or
C.sub.1-4 alkylcarbonyl;
(r) a group --(CH.sub.2).sub.k --COR.sup.18, wherein k is an integer of 1-4, and R.sup.18 represents
hydrogen,
C.sub.1-12 alkyl optionally substituted by hydroxyl, C.sub.3-7 cycloalkyl or C.sub.1-4 alkoxy, or
phenyl optionally substituted by halogen, hydroxyl, nitro, C.sub.1-4 alkyl or C.sub.1-4 alkoxy;
(s) a group --(CH.sub.2).sub.j --COOR.sup.19, wherein j is an integer of 0-4, and R.sup.19 represents
hydrogen,
C.sub.1-12 alkyl optionally substituted by halogen, hydroxyl or
C.sub.1-4 alkoxy, or benzyl, of which the hydrogen atoms on the benzene ring may be optionally substituted by C.sub.3-7 cycloalkyl, C.sub.2-4 alkenyl, halogen, hydroxyl, nitro, C.sub.1-4 alkyl or C.sub.1-4 alkoxy, or a protective group of carboxyl;
(t) a group --(CH.sub.2).sub.p --NR.sup.20 R.sup.21, wherein p is an integer of 0-4, and R.sup.20 and R.sup.21 may be the same or different and represent
(1) hydrogen,
(2) C.sub.1-6 alkyl optionally substituted by hydroxyl, amino (which may be optionally substituted by C.sub.1-4 alkyl, C.sub.1-6 alkylcarbonyl, benzoyl, .alpha.-naphthoyl, .beta.-naphthoyl or sulfonyl), C.sub.3-7 cycloalkyl or C.sub.1-4 alkoxy,
(3) phenyl C.sub.1-4 alkyl, of which the hydrogen atoms on the benzene ring may be optionally substituted by halogen, hydroxyl, nitro, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or carboxyl,
(4) a group --COR.sup.27, wherein R.sup.27 represents
hydrogen,
C.sub.1-4 alkyl optionally substituted by hydroxyl or carboxyl, or
C.sub.3-7 cycloalkyl optionally substituted by hydroxyl or carboxyl, or
(5) a group --SO.sub.2 R.sup.28, wherein R.sup.28 represents
C.sub.1-4 alkyl,
phenyl optionally substituted by halogen, hydroxyl, nitro, cyano, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or carboxyl, or amino optionally substituted by C.sub.1-4 alkyl, C.sub.1-6 alkylcarbonyl, benzoyl, .alpha.-naphthoyl, .beta.-naphthoyl or
sulfonyl, or
(6) a saturated or unsaturated 5-7 membered heterocyclic ring formed by R.sup.20 and R.sup.21 together with the nitrogen atom R.sup.20 and R.sup.21 attached thereto, which heterocyclic ring may further contain one or more of oxygen atoms, nitrogen atoms or sulfur atoms, which heterocyclic ring is selected from the group consisting of piperazino, piperidino, morpholino, succinimido, indolyl, isoindolyl, phthalimido and benzothiazolyl and may be optionally substituted by C.sub.1-4 alkyl or carbonyl;
(u) a group --(CH.sub.2).sub.q --CONR.sup.22 R.sup.23, wherein
q is an integer of 0-4, and
R.sup.22 and R.sup.23 may be the same or different and represent hydrogen,
C.sub.1-6 alkyl (optionally substituted by C.sub.3-7 cycloalkyl), C.sub.3-7 cycloalkyl,
phenyl (optionally substituted by hydroxyl, C.sub.1-4 alkyl or C.sub.1-4 alkoxy),
sulfonyl, or
a saturated or unsaturated 5-7 membered heterocyclic ring formed by R.sup.22 and R.sup.23 together with the nitrogen atom R.sup.22 and R.sup.23 attached thereto, which heterocyclic ring may further contain one or more of oxygen atoms, nitrogen atoms or sulfur atoms, which heterocyclic ring is selected from the group consisting of piperazino, piperidino, morpholino, succinimido, indolyl, isoindolyl, phthalimido and benzothiazolyl and may be optionally substituted by C.sub.1-4 alkyl;
(v) a group --NR.sup.29 R.sup.30, wherein R.sup.29 and R.sup.30, which may be the same or different, represent
(1) hydrogen,
(2) C.sub.1-6 alkyl optionally substituted by
halogen,
hydroxyl,
C.sub.1-4 alkoxy, or
amino which may be optionally substituted by C.sub.1-4 alkyl, C.sub.1-6 alkylcarbonyl, benzoyl, .alpha.-naphthoyl, .beta.-naphthoyl or sulfonyl,
(3) phenyl C.sub.1-4 alkyl, of which the hydrogen atoms on the benzene ring may be optionally substituted by halogen, hydroxyl, nitro, cyano, C.sub.1-4 alkyl or C.sub.1-4 alkoxy,
(4) a group --COR.sup.31, wherein R.sup.31 represents
hydrogen,
C.sub.1-6 alkyl optionally substituted by halogen, hydroxyl, C.sub.1-4 alkyl or C.sub.1-4 alkoxy, or
phenyl optionally substituted by halogen, hydroxyl, nitro, cyano, C.sub.1-4 alkyl or C.sub.1-4 alkoxy,
(5) a group --COOR.sup.32, wherein R.sup.32 represents
C.sub.1-6 alkyl, or
phenyl which may be optionally substituted by halogen, hydroxyl, nitro, cyano, C.sub.1-4 alkyl or C.sub.1-4 alkoxy,
(6) a group --CONR.sup.34 R.sup.35, wherein R.sup.34 and R.sup.35 may be the same or different and represent
hydrogen,
C.sub.1-6 alkyl optionally substituted by C.sub.1-4 alkyl or amino which may be optionally substituted by C.sub.1-4 alkyl, C.sub.1-6 alkylcarbonyl, benzoyl, .alpha.-naphthoyl, .beta.-naphthoyl or sulfonyl, or phenyl, or
(7) a group SO.sub.2 R.sup.36, wherein R.sup.36 represents
C.sub.1-6 alkyl,
phenyl optionally substituted by C.sub.1-4 alkyl, C.sub.1-4 alkoxy or halogen, or
.alpha.- or .beta.-naphthyl,
or a pharmacologically acceptable salt thereof.

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Tricyclic benzazepine and benzothiazepine derivatives

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Tricyclic benzazepine and benzothiazepine derivatives

Life of this patent

Abstract

Claims18