Novel compounds of the following general formula or salts thereof.

The present invention relates to novel cyclic compounds having an excellent tachykinin receptor antagonistic effect, and a method for producing them, as well as a composition containing the foregoing cyclic compounds.
Capsaicine is a stimulative essential component to be in a capsicum, and this is known as a substance which selectively stimulates C-fibers comprising substance P (hereinafter simply referred to as SP), neurokinin A (NKA), calcitonin gene-related peptides (CGRP), etc. of the primary sensory nerve to thereby liberate such intrinsic neuropeptides.
Tachykinin is a generic term for a group of neuropeptides. Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) are known in mammals, and it is known that these peptides bind to the corresponding receptors (neurokinin-1, neurokinin-2, neurokinin-3) that exist in living body to thereby exhibit various biological activities.
Of such neuropeptides, substance P has the longest history and has been studied in detail. In 1931, the existence of substance P in the extract from equine intestines was confirmed, and its structure was determined in 1971. Substance P is a peptide consisting of 11 amino acids. It is known that substance P plays an important role in the peripheral and central nervous systems as an information transmitter substance or the like. In addition, it is considered that substance P participates in various disorders (for example, pain, inflammation, allergy, pollakisuria, urinary incontinence, respiratory tract disorders, psycosis, etc.)
Substance P is broadly distributed over the central and peripheral nervous systems, while having, in addition to the function as a transmitter substance for primary sensory neurons, various physiological activities for vasodilation, promotion of vascular extravasation, contraction of smooth muscles, neuronal excitatory activity, salivation, promotion of diuresis, immunological enhancement, etc. In particular, it is known that SP liberated from the terminal of the spinal (dorsal) horn due to a pain impulse transmits the pain to secondary neurons and that SP liberated from the peripheral terminal induces an inflammatory response in the nociceptive field. In addition, it is considered that SP is involved in Alzheimer type dementia [see review article: Physiological Reviews, Vol. 73, pp. 229-308, (1993); Journal of Autonomic Pharmacology, Vol. 13, pp. 23-93, (1993)].
At present, the following compounds have been known as those having a substance P receptor antagonistic effect.
(1) In Japanese Patent Laid-Open No. 1-287095, disclosed are compounds of a formula:
R1-A-D-Trp(R2)-Phe-R3
wherein R1 represents a hydrogen atom or an amino-protecting group; R2 represents a hydrogen atom, an amino-protecting group, a carbamoyl-(lower)alkyl group, a carboxy-(lower)alkyl group, or a protected carboxy-(lower)alkyl group; R3 represents an ar-(lower)alkyl group, a group of a formula:
wherein R4 and R5 represent, independently, a hydrogen atom, an aryl group or an optionally substituted lower alkyl group, or R4 and R5 are bonded to each other to form a benzene-condensed lower alkylene group, or a group of a formula:
xe2x80x94OR6
wherein R6 represents a hydrogen atom, an aryl group or an optionally substituted lower alkyl group; A represents a single bond or one or two amino acid residues, provided that when A is one amino acid residue of -D-Trp-, R4 is not be a hydrogen atom, and a salt thereof.
(2) In EP-A-436,334, disclosed are compounds of a formula:
(3) In EP-A-429,366, disclosed are compounds of a formula:
(4) In Journal of Medicinal Chemistry, Vol. 34, p. 1751 (1991), disclosed are compounds of a formula:
(5) In WO91/09844, disclosed are compounds of a formula:
(6) In EP-A-522,808, disclosed are compounds of a formula:
(7) In WO93/01169, disclosed are compounds of a formula:
(8) In EP-A-532,456, disclosed are compounds of a formula:
(9) In Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1903 (1994), disclosed is a compound of a formula:
(10) In European Journal of Pharmacology, Vol. 250, p. 403 (1993), disclosed is a compound of a formula:
(11) In EP-A-585,913, disclosed are compounds of a formula:
xe2x80x83wherein
Ring A may be optionally substituted;
Ring B represents an optionally substituted benzene ring;
one of X and Y represents xe2x80x94NR1xe2x80x94 (where R1 represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group), xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, while the other represents xe2x80x94COxe2x80x94, xe2x80x94CSxe2x80x94 or xe2x80x94C(R2)R2axe2x80x94 (where R2 and R2a represent, independently, a hydrogen atom or an optionally substituted hydrocarbon group); or one of these represents xe2x80x94Nxe2x95x90, while the other represents xe2x95x90CR3xe2x80x94 (where R3 represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted amino group, a substituted hydroxyl group, or a mercapto group optionally substituted by an optionally substituted hydrocarbon group);
xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 represents a single bond or a double bond;
Z represents xe2x95x90CR4xe2x80x94 (where R4 represents a hydrogen atom, a hydroxyl group or an optionally substituted hydrocarbon group) or a nitrogen atom, when xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 adjacent to Z is a single bond, and represents a carbon atom when xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 adjacent to Z is a double bond;
D represents a C1-3 alkylene group optionally substituted by oxo or thioxo group(s), or D and Y may together form a 5- to 7-membered ring optionally substituted by oxo or thioxo group(s);
E represents xe2x80x94NR5xe2x80x94 (where R5 represents a hydrogen atom, or an optionally substituted hydrocarbon group, or R5 and Y may together form a 5- to 7-membered ring optionally substituted by oxo or thioxo group(s)), xe2x80x94Oxe2x80x94 or xe2x80x94S(O)nxe2x80x94 (where n represents 0, 1 or 2);
G represents a bond or a C1-3 alkylene group;
Ar represents an optionally substituted aryl group or an optionally substituted heterocyclic group;
provided that (i) when xe2x80x94Xxe2x80x94Yxe2x80x94 is xe2x80x94Oxe2x80x94COxe2x80x94 or xe2x80x94COxe2x80x94Oxe2x80x94, D is xe2x80x94COxe2x80x94 and E is xe2x80x94NR5xe2x80x94, then (a) G is a C1-3 alkylene group, and Ar is a substituted aryl group or a substituted heterocyclic group, or (b) G is a bond, and
R5 is an optionally substituted hydrocarbon group, and (ii) when xe2x80x94Xxe2x80x94Yxe2x80x94 is xe2x80x94NHxe2x80x94COxe2x80x94, then D is xe2x80x94COxe2x80x94, or a salt thereof, etc.
On the other hand, the following compounds have been known as those having a neurokinin-A receptor antagonistic effect.
(1) In Life Sciences, Vol. 50, PL101 (1992), disclosed are compounds of a formula:
(2) In Bioorganic and Medicinal Chemistry Letters, Vol. 10 4, P.1951 (1994), disclosed are compounds of a formula:
(3) In AFMC International Medicinal Chemistry Symposium (Tokyo), P6M139 (1995.9), disclosed are compounds of a formula:
(4) In Tachykinins (Florence), P.21 (1995.10), disclosed are compounds of a formula:
(5) In Journal of Medicinal Chemistry, Vol. 38, P.3772 (1995), disclosed are compounds of a formula:
(6) In Bioorganic and Medicinal Chemistry Letters, Vol. 5, P.2879 (1995), disclosed are compounds of a formula:
However, these references do not disclose condensed heterocyclic compounds having a basic skeleton of a formula:
wherein
Ring M is a heterocyclic ring having xe2x80x94Nxe2x95x90C less than , xe2x80x94COxe2x80x94N less than  or xe2x80x94CSxe2x80x94N less than  as the partial structure xe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than ;
Ra and Rb are bonded to each other to form Ring A, or they are the same or different and represent, independently, a hydrogen atom or a substituent on the Ring M;
Ring A and Ring B represent, independently, an optionally substituted homocyclic or heterocyclic ring, and at least one of them is an optionally substituted heterocyclic ring; and
Ring Z is an optionally substituted nitrogen-containing heterocyclic ring. Nor do these references disclose the properties of such compounds.
At present, compounds which have excellent tachykinin receptor antagonistic effects (especially, substance P and NKA receptor antagonistic effects) and are sufficiently satisfactory as medicines for the above-mentioned various disorders (especially, pollakisuria, urinary incontinence, etc.) from the viewpoint of the safety of themselves and the persistency of their effects have not been found as of yet. Therefore, it is desired to develop compounds which have chemical structures different from those of the above-mentioned known compounds and which have an excellent tachykinin receptor antagonistic effect and are therefore sufficiently satisfactory as medicines for such disorders.
Accordingly, the object of the present invention is to provide novel compounds having high tachykinin receptor antagonistic effects (especially, substance P and NKA receptor antagonistic effects) and a method for producing them, etc.
The other object of the present invention is to provide pharmaceutical compositions having a high tachykinin receptor antagonistic effects (especially, a substance P and NKA receptor antagonistic effects), tachykinin receptor antagonists and ameliorative preparations for disorders of micturition, etc.
The present inventors have assiduously studied in consideration of the above-mentioned situation and, as a result, have synthesized for the first time condensed heterocyclic compounds having, as the basic skeleton, a partial chemical structure of a formula:
wherein the symbols have the same meanings as mentioned above, and have found unexpectedly that these condensed heterocyclic compounds have excellent tachykinin receptor antagonistic effects (especially, substance P and NKA receptor antagonistic effects) as based on their peculiar chemical structures and are sufficiently satisfactory as medicines. On the basis of these findings, the present inventors have completed the present invention.
Specifically, the present invention relates to
(1) A compound of the formula (I):
wherein
ring M is a heterocyclic ring having xe2x80x94Nxe2x95x90C less than , xe2x80x94COxe2x80x94N less than  or xe2x80x94CSxe2x80x94N less than  as the partial structure xe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than ;
Ra and Rb are bonded to each other to form Ring A, or they are the same or different and represent, independently, a hydrogen atom or a substituent on the Ring M;
Ring A and Ring B represent, independently, an optionally substituted homocyclic or heterocyclic ring, and at least one of them is an optionally substituted heterocyclic ring;
Ring C is an optionally substituted homocyclic or heterocyclic ring;
Ring Z is an optionally substituted nitrogen-containing heterocyclic ring; and
n is an integer of 1 to 6, or a salt thereof,
(2) A compound as described in (1), wherein
Ra and Rb are the same or different and represent, independently,
(i) a hydrogen atom,
(ii) a C1-6 alkyl group optionally having from 1 to 5 substituents selected from
(a) a hydroxyl group,
(b) a C1-6 alkoxy group,
(c) a C1-6 alkylthio group,
(d) an amino group,
(e) a C1-7 acylamino group,
(f) a carboxyl group,
(g) a nitro group,
(h) a mono- or di-C1-6 alkylamino group,
(i) a mono- or di-C3-8 cycloalkylamino group,
(j) a C6-10 arylamino group,
(h) a 5-membered to 9-membered cyclicamino group which may have 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms,
(1) a 5-membered to 6-membered aromatic heterocyclic group having from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, in addition to carbon atoms,
(m) a 5-membered to 9-membered non-aromatic heterocyclic ring having from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, in addition to carbon atoms,
(n) a C1-4 alkylsulfonylamino group,
(o) a C1-6 alkyl-carbonyloxy group and
(p) a halogen atom,
(iii) an optionally halogenated C1-6 alkoxy group,
(iv) an optionally halogenated C1-6 alkylthio group,
(v) a C3-10 cycloalkyl group,
(vi) a C6-10 aryl group,
(vii) a C1-7 acylamino group,
(viii) a C1-3 acyloxy group,
(ix) a hydroxy group,
(x) a nitro group,
(xi) a cyano group,
(xii) an amino group,
(xiii) a mono- or di-C1-6 alkylamino group,
(xiv) a 5-membered to 9-membered cyclicamino group which may have 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, in addition to one nitrogen atom,
(xv) a C1-6 alkylcarbonylamino group,
(xvi) a C1-6 alkylsulfonylamino group,
(xvii) a C1-6 alkoxycarbonyl group,
(xviii) a carboxyl group,
(xix) a C1-6 alkylcarbonyl group,
(xx) a carbamoyl group,
(xxi) a mono- or di-C1-6 alkylcarbamoyl group,
(xxii) C1-6 alkylsulfonyl group, or
(xxiii) an oxo group; or
Ra and Rb are bonded to each other to form Ring A, and the Ring A is a 5-membered to 6-membered aromatic group having from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, in addition to carbon atoms, a 5-membered to 9-membered non-aromatic heterocyclic group having from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, in addition to carbon atoms, or a 3-membered to 10-membered cyclic hydrocarbon group each of which may have 1 to 4 substituents selected from
(i) a halogen atom,
(ii) a C1-6 alkyl group optionally having from 1 to 5 substituents selected from
(a) a hydroxyl group,
(b) an amino group,
(c) a carboxyl group,
(d) a nitro group,
(e) a mono- or di-C1-6 alkylamino group,
(f) a C1-6 alkyl-carbonyloxy group and
(g) a halogen atom,
(iii) an optionally halogenated C1-6 alkoxy group,
(iv) an optionally halogenated C1-6 alkylthio group,
(v) a C6-10 aryl group,
(vi) a C1-7 acylamino group,
(vii) a C1-3 acyloxy group,
(viii) a hydroxy group,
(ix) a nitro group,
(x) a cyano group,
(xi) an amino group,
(xii) a mono- or di-C1-6 alkylamino group,
(xiii) a 5-membered to 9-membered cyclicamino group which may have 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, in addition to one nitrogen atom,
(xiv) a C1-6 alkylcarbonylamino group,
(xv) a C1-6 alkylsulfonylamino group,
(xvi) a C1-6 alkoxycarbonyl group,
(xvii) a carboxyl group,
(xviii) a C1-6 alkylcarbonyl group,
(xix) a carbamoyl group,
(xx) a mono- or di-C1-6 alkylcarbamoyl group,
(xxi) a C1-6 alkylsulfonyl group, or
(xxii) an oxo group;
the Ring B is a 5-membered to 6-membered aromatic group having from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, in addition to carbon atoms, a 5-membered to 9-membered non-aromatic heterocyclic group having from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, in addition to carbon atoms, or a 3-membered to 10-membered cyclic hydrocarbon group each of which may have 1 to 4 substituents selected from
(i) a halogen atom,
(ii) a C1-6 alkyl group optionally having from 1 to 5 substituents selected from
(a) a hydroxyl group,
(b) an amino group,
(c) a carboxyl group,
(d) a nitro group,
(e) a mono- or di-C1-6 alkylamino group,
(f) a C1-6 alkyl-carbonyloxy group and
(g) a halogen atom,
(iii) an optionally halogenated C1-6 alkoxy group,
(iv) an optionally halogenated C1-6 alkylthio group,
(v) a C6-10 aryl group,
(vi) a C1-7 acylamino group,
(vii) a C1-3 acyloxy group,
(viii) a hydroxy group,
(ix) a nitro group,
(x) a cyano group,
(xi) an amino group,
(xii) a mono- or di-C1-6 alkylamino group,
(xiii) a-5-membered to 9-membered cyclicamino group which may have 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, in addition to one nitrogen atom,
(xiv) a C1-6 alkylcarbonylamino group,
(xv) a C1-6 alkylsulfonylamino group,
(xvi) a C1-6 alkoxycarbonyl group,
(xvii) a carboxyl group,
(xviii) a C1-6 alkylcarbonyl group,
(xix) a carbamoyl group,
(xx) a mono- or di-C1-6 alkylcarbamoyl group,
(xxi) a C1-6 alkylsulfonyl group, and
(xxii) an oxo group;
the Ring C is a 5-membered to 10-membered heterocyclic group which may have 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms which optionally having 1 to 5 substituents selected from
(i) a halogen atom,
(ii) an optionally halogenated C1-10 alkyl group,
(iii) an amino-substituted C1-4 alkyl group,
(vi) a mono- or di-C1-4 alkylamino-substituted C1-4 alkyl group,
(v) a carboxyl-substituted C1-4 alkyl group,
(vi) a C1-4 alkoxy-carbonyl-substituted C1-4 alkyl group,
(vii) a hydroxy-substituted C1-4 alkyl group,
(viii) a C1-4 alkoxy-carbonyl-substituted C1-4 alkyl group,
(ix) a C3-10 cycloalkyl group,
(x) a nitro group,
(xi) a cyano group,
(xii) a hydroxyl group,
(xiii) an optionally-halogenated C1-10 alkoxy group,
(xiv) an optionally-halogenated C1-4 alkylthio group,
(xv) an amino group,
(xvi) a mono- or di-C1-4 alkylamino group,
(xvii) a 5-membered to 9-membered cyclic amino group optionally having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, in addition to one nitrogen atom,
(xviii) a C1-4 alkyl-carbonylamino group,
(xix) an aminocarbonyloxy group,
(xx) a mono- or di-C1-4 alkylaminocarbonyloxy group,
(xxi) a C1-4 alkylsulfonylamino group,
(xxii) a C1-4 alkoxy-carbonyl group,
(xxiii) an aralkyloxycarbonyl group,
(xxiv) a carboxyl group,
(xxv) a C1-6 alkyl-carbonyl group,
(xxvi) a C3-6 cycloalkyl-carbonyl group,
(xxvii) a carbamoyl group,
(xxviii) a mono- or di-C1-4 alkylcarbamoyl group,
(xxix) a C1-6 alkylsulfonyl group and
(xxx) a 5-membered or 6-membered aromatic monocyclic heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, which may have 1 to 3 substituents selected from an optionally halogenated C1-4 alkyl; or
a 3-membered to 10-membered cyclic hydrocarbon group, optionally having 1 to 5 substituents selected from
(i) a halogen atom,
(ii) an optionally halogenated C1-10 alkyl group,
(iii) an amino-substituted C1-4 alkyl group,
(iv) a mono- or di-C1-4 alkylamino-substituted C1-4 alkyl group,
(v) a carboxyl-substituted C1-4 alkyl group,
(vi) a hydroxy-substituted C1-4 alkyl group,
(vii) a C1-4 alkoxy-carbonyl-substituted C1-4 alkyl group,
(viii) a C3-10 cycloalkyl group,
(ix) a nitro group,
(x) a cyano group,
(xi) a hydroxyl group,
(xii) an optionally-halogenated C1-10 alkoxy group,
(xiii) an optionally-halogenated C1-4 alkylthio group,
(xiv) an amino group,
(xv) a mono- or di-C1-4 alkylamino group,
(xvi) a 5-membered to 9-membered cyclic amino group optionally having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, in addition to one nitrogen atom,
(xvii) a C1-4 alkyl-carbonylamino group,
(xviii) an aminocarbonyloxy group,
(xiv) a mono- or di-C1-4 alkylaminocarbonyloxy group,
(xx) a C1-4 alkylsulfonylamino group,
(xxi) a C1-4 alkoxy-carbonyl group,
(xxii) an aralkyloxycarbonyl group,
(xxiii) a carboxyl group,
(xxiv) a C1-6 alkyl-carbonyl group,
(xxv) a C3-6 cycloalkyl-carbonyl group,
(xxvi) a carbamoyl group,
(xxvii) a mono- or di-C1-4 alkylcarbamoyl group,
(xxviii) a C1-6 alkylsulfonyl group and
(xxix) a 5-membered or 6-membered aromatic monocyclic heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, which may have 1 to 3 substituents selected from an optionally halogenated C1-4 alkyl;
the Ring Z is a 5-membered to 12-membered heterocyclic ring optionally having at least one hetero atom selected from nitrogen, oxygen and sulfur atoms, in addition to Y and the nitrogen atom, having 1 to 5 substituents selected from
(i) a C1-6 alkyl group,
(ii) a C2-6 alkenyl group,
(iii) a C2-6 alkynyl group,
(iv) a C3-8 cycloalkyl group,
(v) a C3-8 cycloalkyl-C1-4 alkyl group,
(vi) a C6-14 aryl group,
(vii) a nitro group,
(viii) a cyano group,
(ix) a hydroxyl group,
(x) a C1-4 alkoxy group,
(xi) a C1-4 alkylthio group,
(xii) an amino group,
(xiii) a mono- or di-C1-4 alkylamino group,
(xiv) a 5-membered to 9-membered cyclic amino group optionally having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, in addition to one nitrogen atom,
(xv) a C1-4 alkyl-carbonylamino group,
(xvi) a C1-4 alkylsulfonylamino group,
(xvii) a C1-4 alkoxy-carbonyl group,
(xviii) a carboxyl group,
(xix) a C1-6 alkyl-carbonyl group,
(xx) a carbamoyl group,
(xxi) a mono- or di-C1-4 alkylcarbamoyl group,
(xxii) a C1-6 alkylsulfonyl group,
(xxiii) an oxo group, and
(xxiv) a thioxo group,
(3) A compound as described in (1), wherein Ra and Rb are bonded to each other to form Ring A, Ring C is an optionally substituted benzene ring or an optionally substituted heterocyclic ring, Ring Z is a nitrogen-containing heterocyclic ring optionally substituted by an oxo group, and n represents 1 or 2,
(4) A compound as described in (1), wherein Ring Z is a nitrogen-containing heterocyclic ring optionally substituted by an oxo group,
(5) A compound as described in (1), wherein one of Ring A and Ring B is an optionally substituted aromatic ring and the other is an optionally substituted aromatic heterocyclic ring,
(6) A compound as described in (1), wherein Ring A is an optionally substituted aromatic heterocyclic ring, and Ring B is an optionally substituted benzene ring,
(7) A compound as described in (6), wherein the aromatic heterocyclic ring is a 5-membered or 6-membered, aromatic heterocyclic ring having one or two hetero atoms selected from nitrogen, sulfur and oxygen atoms, in addition to carbon atoms,
(8) A compound as described in (1), wherein Ring C is an optionally substituted benzene ring,
(9) A compound as described in (1), wherein Ring C is a benzene ring which may have from 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-6 alkyl group and an optionally halogenated C1-6 alkoxy group,
(10) A compound as descrobed in (1), wherein Ring Z is a 5-membered to 10-membered ring optionally substituted by 1 or 2 oxo groups,
(11) A compound as descrobed in (1), wherein xe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than  is xe2x80x94Nxe2x95x90C less than  or xe2x80x94COxe2x80x94N less than ,
(12) A compound as descrobed in (1), wherein n is 1,
(13) A compound as described in (1), wherein Ring A is an optionally substituted pyridine ring, Ring B is an optionally substituted benzene ring, Ring C is an optionally substituted benzene ring, Ring Z is a 5-membered to 10-membered ring optionally substituted by an oxo group, xe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than  is xe2x80x94COxe2x80x94N less than , and n is 1,
(14) A compound as described in (1), wherein Ra and Rb are the same or different and represent, independently, a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an optionally halogenated alkoxy group, an optionally halogenated alkylthio group, a cycloalkyl group, an aryl group, an acylamino group, an acyloxy group, a hydroxy group, a nitro group, a cyano group, an amino group, a mono- or di-alkylamino group, a cyclic amino group, an alkylcarbonylamino group, an alkylsulfonylamino group, an alkoxycarbonyl group, a carboxyl group, an alkylcarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsulfonyl group or an oxo group,
(15) A compound as described in (1), wherein Ra and Rb are the same or different and represent, independently,
(i) a hydrogen atom,
(ii) a C1-6 alkoxy-C1-6 alkyl group,
(iii) a C1-6 alkylthio-C1-6 alkyl group,
(iv) an amino-C1-6 alkyl group,
(v) a C1-7 acylamino-C1-6 alkyl group,
(vi) a mono- or di-C-1-6 alkylamino-C1-4 alkyl group,
(vii) C3-10 cycloamino-C1-6 alkyl group,
(viii) a C1-6 alkyl group having 5-membered or 6-membered cycloamino optionally substituted by C1-6 alkyl group,
(ix) a C1-6 alkylsulfonylamino-C1-6 alkyl group, or
(x) a C1-6 alkylcarbonyloxy-C1-6 alkyl; or
Ra and Rb are bonded to each other to form pyridine ring which is optionally substituted by 1 to 3 substituents selected from a halogen atom and a C1-4 alkyl group;
Ring B is a benzene ring optionally having 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-4 alkyl group and an optionally halogenated C1-4 alkoxy group;
Ring C is a benzene ring optionally having 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-4 alkoxy group, an amino group optionally substituted by C1-4 alkyl group, a C1-3 acyloxy group and a hydroxyl group;
Ring Z is a 5-membered to 10-membered nitrogen containing heterocyclic ring optionally having an oxo group and optionally substituted by a C1-4 alkyl group or a hydroxyl group; xe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than  is xe2x80x94Nxe2x95x90C less than  or xe2x80x94COxe2x80x94N less than ; and n is an integer of 1,
(16) A compound as described in (15), wherein Ra and Rb are bonded to each other to form Ring A, and xe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than  is xe2x80x94COxe2x80x94N less than ,
(17) A compound as described in (16), wherein the Ring A is an unsubstituted pyridine ring,
(18) A compound as described in (16), wherein the Ring B is a benzene ring which optionally substituted by an optionally halogenated C1-4 alkyl group,
(19) A compound as described in (16), wherein the Ring C is an benzene ring which may have 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-4 alkyl group and an optionally halogenated C1-4 alkoxy group,
(20) A compound as described in (16) wherein Ring Z is
wherein, m and p are the same or different and represent, independently, an integer of from 1 to 5, Z1 and Z2 are the same or different and represent, independently, an hydrogen atom, an C1-4 alkyl group or a hydroxyl group and Y is the same meaning as described in (15),
(21) A compound as described in (1), which is (9S)-7-[3,5-bis(trifluoromethyl)benzyl]-6,7,8,9,10,12-hexahydro-9-methyl-6,12-dioxo-5-phenyl[1,4]diazepino[2,1-g][1,7]naphthyridine,
(22) A compound as described in (1), which is (9s)-7-[3,5-bis(trifluoromethyl)benzyl]-6,7,8,9,10,12-hexahydro-9-methyl-5-(4-methylphenyl)-6,12-dioxo[1,4]diazepino[2,1-g][1,7]naphthyridine,
(23) A compound as described in (1), which is (9R)-7-[3,5-bis(trifluoromethyl)benzyl]-6,7,8,9,10-11-hexahydro-9-methyl-6,13-dioxo-5-phenyl-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine,
(24) A compound as described in (1), which is (9R)-7-[3,5-bis(trifluoromethyl)benzyl]-6,7,8,9,10,11-hexahydro-9-methyl-5-(4-methylphenyl)-6r13-dioxo-13H-[1,4]diazocino[2,1-g][1,7]naphthyridine,
(25) A process for producing a compound as described in (1), characterized by cyclizing a compound of a formula:
wherein D and E represent groups from which ring Z as set forth in claim 1 is formed via the nitrogen atom adjacent to E, L represents a leaving group, and the other symbols are the same meanings as those described in (1), or a salt thereof,
(26) A pharmaceutical composition comprising a compound as described in (1),
(27) A composition for antagonizing tachykinin receptor compries a compound as described in (1),
(28) A composition for antagonizing Substance P receptor comprises a compound as described in (1),
(29) A composition for antagonizing neurokinin A receptor comprises a compound as described in (1),
(30) A pharmaceutical composition for preventing or treating disorders of micturition which comprises a compound as described in (1) and a pharmaceutical acceptable carrier thereof,
(31) A pharmaceutical composition for preventing or treating disorders of asthma, rheumatoid arthritis, osteoarthritis, pain, migraine, cough, irritable bowel syndrome or emesis, which comprises a compound as described in (1) and a pharmaceutical acceptable carrier thereof,
(32) A method for antagonizing tachykinin receptor in mammals which comprises administrating to a subject in need, an effective amount of a compound as described in (1),
(33) A method for preventing or treating disorders of micturition in mammals which comprises administrating to a subject in need an effective amount of a compound as described in (1),
(34) A method for preventing or treating disorders of asthma, migraine, irritable bowel syndrome, pain, cough or emesis in mammals which comprises administrating to a subject in need an effective amount of a compound as described in (1),
(35) Use of a compound as described in (1) for manufacturing a composition for antagonizing a tachykinin receptor,
(36) Use of a compound as described in (1) for manufacturing a pharmaceutical composition for treating disorders of micturition, and
(37) Use of a compound as described in (1) for manufacturing a pharmaceutical composition for treating disorders of asthma, micturition, irritable bowel syndrome, pain, cough or emesis.
The compounds of the above-mentioned (1) include compounds of a formula (Ia):
wherein ring A is formed by Ra and Rb are bonded to each other to form Ring A, and the other symbols have the same meanings as above.
The present invention is described in detail hereinunder.
Regarding xe2x80x9cRing M, X and Yxe2x80x9d
In the above-mentioned formulae (I) and (Ia), Ring M is a heterocyclic ring having xe2x80x94Nxe2x95x90C less than , xe2x80x94COxe2x80x94N less than  or xe2x80x94CSxe2x80x94N less than  as the partial structure xe2x80x9cxe2x80x94X{overscore (xe2x80x94)} Y less than xe2x80x9d. Preferably, Ring M has xe2x80x94COxe2x80x94N less than  or xe2x80x94Nxe2x95x90Cxe2x80x94 as the partial structure xe2x80x9cxe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than xe2x80x9d.
Regarding xe2x80x9cRa and Rbxe2x80x9d
In the above-mentioned formulae (I) and (Ia), Ra and Rb are bonded to each other to form Ring A, or these are the same or different and represent, independently, a hydrogen atom or a substituent on the Ring M.
The substituents Ra and Rb on the Ring M include, for example, a halogen atom, an optionally substituted alkyl group, an optionally halogenated alkoxy group, an optionally halogenated alkylthio group, a cycloalkyl group, an aryl group, an acylamino group, an acyloxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a mono- or di-alkylamino group, a cyclic amino group (e.g., a cyclic amino group optionally containing hetero atom(s) of oxygen atom, sulfur atom, etc., in addition to nitrogen atom), an alkylcarbonylamino group, an alkylsulfonylamino group, an alkoxycarbonyl group, a carboxyl group, an alkylcarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsulfonyl group, an oxo group, etc.
The above-mentioned xe2x80x9chalogen atomxe2x80x9d includes, for example, fluorine, chlorine, bromine and iodine atoms. Preferably, the halogen atom includes, for example, fluorine, chlorine and bromine atoms.
The xe2x80x9coptionally substituted alkyl groupxe2x80x9d includes, for example, C1-6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups, etc.) optionally having from 1 to 5 substituents selected from a hydroxyl group, a C1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), a C1-6 alkylthio group (e.g., methylthio, ethylthio, propylthio, butylthio, isobutylthio, sec-butyltio, tert-butyltio, etc.), an amino group, a C1-7 acylamino group (e.g. formylamino, acethyl amino, propyonyl amino, butylyl amino, benzoyl amino, etc.), an N-alkylamino group, a carboxyl group, a nitro group, a mono- or di-C1-6 alkylamino group (e.g., methylamino, ethylamino, dimethylamino and diethylamino groups, etc.), an optionally substituted N-substituted amino group substituted by one or two homocyclic groups (e.g., mono- or di- C3-8 cycloalkylamino groups, for example, cyclopropylamino, cyclobutylamino, cyclohexylamino; C6-10 arylamino groups, for example, phenylamino, etc.), an optionally substituted heterocyclic groups [e.g., 5-membered to 9-membered cycloamino groups which may have 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms (e.g., 5-membered or 6-membered non-aromatic cycloamino groups, for example, piperidyno, 4-methylpiperodyno, morpholino, thiomorpholino, piperadinyl, 4-methylpiperadinyl, 4-ethylpiperadinyl, pyrrolidinyl, imidazolydinyl, pyrazolydinyl; 5-membered or 6-membered aromatic cycloamino groups, for example, pyridyl, pyradyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazulyl, etc.), aromatic heterocyclic rings (e.g., thiophenyl, furanyl, thiazolyl, isothiazolyl, oxazolyl, etc.), non-aromatic heterocyclic rings (e.g., tetrohydropyridyl, dihydropyridyl, tetrahydropyradyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, dihydropyrrolyl, dyhydroimidazolyl, dihydropyrazolyl, dihydrothiophenyl, dihydrofuranyl, dihydrooxazolyl, dihydroisooxazolyl, hexahydropyrimidinyl, hexahydropyridazinyl, tetrahydropyranyl, pyrazolydinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, etc.)], an alkylsulfonylamino groups (e.g. C1-4 alkylsulfonylamino groups, for example, methylsulfonylamino, ethylsulfonylamino, etc.), a C1-6 alkyl-carbonyloxy group (e.g., acetoxy and ethylcarbonyloxy groups, etc.) and a halogen atom (e.g., fluorine, chlorine and bromine atoms, etc.), etc. Preferably, the xe2x80x9coptionally substituted alkyl groupxe2x80x9d includes C1-6 alkyl groups optionally substituted by from 1 to 4 or so halogen atoms, especially optionally halogenated C1-4 alkyl groups (e.g., C1-4 alkyl groups and C1-4 alkyl groups substituted by from 1 to 3 or so halogen atoms, etc., such as methyl, chloromethyl, fluoromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 1-(trifluoromethyl)ethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl and tert-butyl groups, etc.). Also preferably, the xe2x80x9coptionally-substituted alkyl groupxe2x80x9d includes C1-6 alkoxy-C1-6 alkyl groups (e.g. C1-4 alkoxy-C1-4 alkyl groups, for example, methoxymethyl, ethoxymethyl, isopropoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, etc.), C1-6 alkyltho-C1-6 alkyl groups (e.g. C1-4 alkylthio-C1-4 alkyl groups, for example, methylthiomethyl, ethylthiomethyl, butylthiomethyl, methylthioethyl, ethylthioethyl, etc.), amino-C1-6 alkyl groups (preferably, amino-C1-4 alkyl groups), for example, aminomethyl, 2-aminoethyl, 2-aminopropyl, 3-aminopropyl, 2-aminobutyl, 3-aminobutyl and 4-aminobutyl groups, C1-7 acylamino-C1-6 alkyl groups (e.g. C1-7 acylamino-C1-4 alkyl groups, for example, formylaminomethyl, acetylaminomethyl, propionylaminomethyl, butylylaminoethyl, benzoylaminomethyl, etc.), etc. And, again, the xe2x80x9coptionally-substituted alkyl groupxe2x80x9d preferably includes mono-C1-4 alkylamino-C1-6 alkyl groups, for example, mono-C1-3 alkylamino-C1-4 alkyl groups, etc., such as methylaminomethyl, ethylaminomethyl, 2-(N-methylamino)ethyl, 2-(N-ethylamino)ethyl, 2-(N-methylamino)propyl, 3-(N-methylamino)propyl, 3-(N-methylamino)butyl and 4-(N-methylamino)butyl groups, C3-10 cycloalkylamino-C1-6 alkyl groups (e.g. C3-10 cycloalkylamino-C1-4 alkyl groups, for example, cyclopropylaminomethyl, cyclobutylaminomethyl, cyclohexylaminomethyl, cyclopropylaminomethyl, cyclobutylaminomethyl, cyclohexylaminomethyl, phenylaminomethyl, etc.), optionally having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms 5-membered or 6-membered non-aromatic cycloamino-C1-6 alkyl groups (e.g. 5-membered or 6-membered non-aromatic cycloamino-C1-4 alkyl groups, for example, piperidinomethyl, 4-methylpiperidinomethyl, morpholinomethyl, thiomorpholinomethyl, piperadinylmethyl, 4-methylpiperadinylmethyl, piperidinoethyl, morpholinoethyl, piperadinylethyl; 5-membered or 6-membered aromatic cycloamino-C1-4 alkyl groups, for example, pyridylmethyl, pyrimidinylmethyl, imidazolylmethyl, pyridylethyl, etc.), C1-6 alkylsulfonylamino-C1-6 alkyl groups (e.g. C1-6 alkylsulfonylamino-C1-4 alkyl groups, for example, methylsulfonylaminomethyl, ethylsulfonylaminomethyl, methylsulfonylaminobutyl, ethylsulfonylaminoethyl, etc.), C1-6 alkyl-carbonyloxy-C1-6 alkyl groups (e.g. C1-4 alkyl-carbonyloxy-C1-4 alkyl groups, for example, methylcarbonyloxymethyl, ethylcarbonyloxymethyl, butylcarbonyloxymethyl, methylcarbonyloxyethyl, ethylcarbonyloxyethyl, etc.), etc.
The xe2x80x9coptionally halogenated alkoxy groupxe2x80x9d includes, for example, C1-6 alkoxy groups or C1-6 alkoxy groups substituted by from 1 to 5 or so halogen atoms, etc. Such alkoxy groups or halogenated alkoxy groups include, for example, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy and hexyloxy groups, etc. Preferably, the xe2x80x9coptionally-halogenated alkoxy groupxe2x80x9d includes C1-4 alkoxy groups or C1-4 alkoxy group substituted by from 1 to 3 or so halogen atoms, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy and sec-butoxy groups, etc.
The xe2x80x9coptionally halogenated alkylthio groupxe2x80x9d includes, for example, C1-6 alkylthio groups, and C1-6 alkylthio groups having from 1 to 5 or so halogen atoms, etc. Such alkylthio groups and halogenated alkylthio groups include, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio groups, etc. Preferably, the xe2x80x9coptionally halogenated alkylthio groupxe2x80x9d includes C1-4 alkylthio groups, or C1-4 alkylthio groups substituted by from 1 to 3 or so halogen atoms, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio and 4,4,4-trifluorobutylthio groups, etc. The xe2x80x9ccycloalkyl groupxe2x80x9d includes C3-10 cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl groups, etc.); the xe2x80x9caryl groupxe2x80x9d includes C6-10 aryl groups (e.g., phenyl group, etc.); the xe2x80x9cacylamino groupxe2x80x9d includes, for example, C1-7 acylamino groups (e.g., formylamino, acetylamino, propionylamino, butyrylamino and benzoylamino groups, etc.), etc. The xe2x80x9cacyloxy groupxe2x80x9d includes, for example, C1-3 acyloxy groups (e.g., formyloxy, acetoxy and propionyloxy groups, etc.), etc. The xe2x80x9cmono- or di-alkylamino groupxe2x80x9d includes, for example, mono- or di-C1-4 alkylamino groups (e.g., methylamino, ethylamino, propylamino, dimethylamino and diethylamino groups, etc.), etc. The xe2x80x9ccyclic amino groupxe2x80x9d includes, for example, 5-membered to 9-membered cyclic amino groups optionally having from 1 to 3 hetero atoms, such as oxygen atom, sulfur atom, etc., in addition to nitrogen atom (e.g., pyrrolidino, piperidino, morpholino and thiomorpholino groups, etc.), etc. The xe2x80x9calkylcarbonylamino groupxe2x80x9d includes, for example, C1-4 alkyl-carbonylamino groups (e.g., acetylamino, propionylamino and butyrylamino groups, etc.); the xe2x80x9calkylsulfonylamino groupxe2x80x9d includes, for example, C1-4 alkylsulfonylamino groups (e.g., methylsulfonylamino and ethylsulfonylamino groups, etc.); the xe2x80x9calkoxycarbonyl groupxe2x80x9d includes, for example, C1-4 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl groups, etc.); the xe2x80x9calkylcarbonyl groupxe2x80x9d includes, for example, C1-6 alkyl-carbonyl groups (e.g., methylcarbonyl, ethylcarbonyl and propylcarbonyl groups, etc.); the xe2x80x9cmono- or di-alkylcarbamoyl groupxe2x80x9d includes for example, mono- or di-C-1-4 alkylcarbamoyl groups (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and diethylcarbamoyl groups, etc.); the xe2x80x9calkylsulfonyl groupxe2x80x9d includes, for example, C1-6 alkylsulfonyl groups (e.g., methylsulfonyl, ethylsulfonyl and propylsulfonyl groups, etc.), etc.
Regarding xe2x80x9cRing A and Ring Bxe2x80x9d
In the above-mentioned formulae (I) and (Ia), Ring A and Ring B represent, independently, an optionally substituted homocyclic or heterocyclic ring, and at least one of these is an optionally substituted heterocyclic ring.
The xe2x80x9chomocyclic or heterocyclic ringxe2x80x9d includes, for example, (i) an aromatic heterocyclic ring or non-aromatic heterocyclic ring having the same one or different hetero atoms selected from nitrogen, sulfur and oxygen atoms, preferably from 1 to 3 such hetero atoms, in addition to carbon atoms, or (ii) a cyclic hydrocarbon ring (homocyclic ring) comprising carbon atoms, etc.
The xe2x80x9caromatic heterocyclic ringxe2x80x9d includes, for example, 5-membered or 6-membered aromatic heterocyclic rings having from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms, in addition to carbon atoms (e.g., pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, thiazole, isothiazole, oxazole and isoxazole rings, etc.), etc. Preferably, the aromatic heterocyclic ring includes, for example, pyridine, pyrazine and thiophene rings, etc., as well as pyrrole and thiazole rings, etc. Especially preferred are (i) 6-membered, nitrogen-containing heterocyclic rings having one or two nitrogen atoms in addition to carbon atoms (e.g., pyridine and pyrazine rings, etc.) or (ii) 5-membered aromatic heterocyclic rings having one sulfur atom in addition to carbon atoms (e.g., thiophene ring, etc.), etc.
The xe2x80x9cnon-aromatic heterocyclic ringxe2x80x9d includes, for example, 5-membered to 9-membered, non-aromatic heterocyclic rings, preferably 5-membered or 6-membered, non-aromatic heterocyclic rings, having from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, etc.
For example, Ring A includes tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyrrole, dihydroimidazole, dihydropyrazole, dihydrothiophene, dihydrofuran, dihydrothiazole, dihydroisothiazole, dihydroxazole and dihydroisoxazole rings, etc.; and Ring A includes, in addition to these rings, piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyran, morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, tetrahydrothiazole, tetrahydroisothiazole, tetrahydroxazole and tetrahydroisoxazole rings, etc. Preferably, Ring A includes, for example, 6-membered, non-aromatic heterocyclic rings having one or two nitrogen atoms in addition to carbon atoms (e.g., tetrahydropyridine, tetrahydropyrimidine and tetrahydropyridazine rings, etc.), etc., and is especially preferably a tetrahydropyridine ring, etc. Preferably, Ring B includes, for example, 6-membered, non-aromatic heterocyclic rings having one or 2 nitrogen atoms in addition to carbon atoms (e.g., piperidine and piperazine rings, etc.), etc., and is especially preferably a piperazine ring, etc.
The xe2x80x9ccyclic hydrocarbon ring (homocyclic ring)xe2x80x9d includes, for example, 3-membered to 10-membered (for example, 5-membered to 9-membered) cyclic hydrocarbon rings, preferably 5-membered or 6-membered cyclic hydrocarbon rings, etc. For example, Ring A includes benzene, C3-10 cycloalkenes (e.g., cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), etc. The cycloalkenes are preferably C5-6 cycloalkenes (e.g., cyclopentene, cyclohexene, etc.), etc. Ring B includes, in addition to these, C3-10 cycloalkanes (e.g., cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.), etc. The cycloalkanes are preferably C5-6 cycloalkanes (e.g., cyclohexane, cyclopentane, etc.), etc. Preferably, Ring A includes, for example, 6-membered homocyclic rings such as benzene and cyclohexene rings, etc. Especially preferred are a benzene ring, etc. Ring B preferably includes, for example, 6-membered homocyclic rings such as benzene and cyclohexane rings, etc. Especially preferred is a benzene ring.
At least one of Ring A and Ring B is an optionally-substituted heterocyclic ring. Both of Ring A and Ring B may be optionally substituted heterocyclic rings. Preferably, one of Ring A and Ring B is 1) an optionally substituted aromatic ring and the other is 2) an optionally substituted aromatic heterocyclic ring.
The above-mentioned 1) xe2x80x9caromatic ringxe2x80x9d includes, for example, (i) the above-mentioned xe2x80x9caromatic heterocyclic ringsxe2x80x9d, namely, optionally substituted, 5-membered or 6-membered, aromatic heterocyclic rings having the same one or different two hetero atoms selected from nitrogen, sulfur and oxygen atoms, preferably from 1 to 3 such hetero atoms, in addition to carbon atoms (e.g., pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, thiazole, isothiazole, oxazole and isoxazole rings, etc.), or (ii) optionally substituted benzene rings.
For the substituents for the above-mentioned 1) xe2x80x9coptionally substituted aromatic ringxe2x80x9d, for example, referred to are the same substituents as those for Ring A and Ring B which are mentioned hereinunder. The xe2x80x9caromatic heterocyclic ringxe2x80x9d of the above-mentioned 2) xe2x80x9coptionally substituted aromatic heterocyclic ringxe2x80x9d includes, for example, the same aromatic heterocyclic rings as those in the above-mentioned xe2x80x9c5-membered or 6-membered, aromatic heterocyclic ringxe2x80x9d. For the substituents for the above-mentioned 2) xe2x80x9coptionally substituted aromatic heterocyclic ringxe2x80x9d, for example, referred to are the same substituents as those for Ring A and Ring B which are mentioned hereinunder. The xe2x80x9c5-membered or 6-membered, aromatic heterocyclic ringxe2x80x9d preferably includes the same heterocyclic rings as those referred to hereinabove for the foregoing xe2x80x9caromatic heterocyclic ringxe2x80x9d.
More preferably, one of Ring A and Ring B is an optionally substituted aromatic heterocyclic ring (e.g., a 5-membered or 6-membered aromatic heterocyclic ring) and the other is an optionally substituted benzene ring.
The substituents for the optionally substituted xe2x80x9chomocyclic or heterocyclic ringxe2x80x9d, xe2x80x9caromatic heterocyclic ringxe2x80x9d, xe2x80x9cnon-aromatic heterocyclic ringxe2x80x9d, xe2x80x9ccyclic hydrocarbon ringxe2x80x9d, xe2x80x9caromatic ringxe2x80x9d and xe2x80x9cbenzene ringxe2x80x9d to be represented by Ring A and Ring B include, for example, a halogen atom, an optionally substituted alkyl group, an optionally halogenated alkoxy group, an optionally halogenated alkylthio group, an aryl group, an acylamino group, an acyloxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a mono- or di-alkylamino group, a cyclic amino group (e.g., a cyclic amino group optionally having hetero atom selected from oxygen atom, sulfur atom, etc., in addition to nitrogen atom), an alkylcarbonylamino group, an alkylsulfonylamino group, an alkoxycarbonyl group, a carboxyl group, an alkylcarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group, an alkylsulfonyl group, an oxo group, etc.
The xe2x80x9chalogen atomxe2x80x9d, which Ring A and Ring B may have, includes, for example, fluorine, chlorine, bromine and iodine atoms. Preferably, the halogen atom includes, for example, fluorine, chlorine and bromine atoms (especially, fluorine and chlorine atoms, etc.).
The xe2x80x9coptionally substituted alkyl groupxe2x80x9d, which Ring A and Ring B may have, includes, for example, C1-6 alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups, etc.) optionally having from 1 to 5 substituents selected from a hydroxyl group, an amino group, a carboxyl group, a nitro group, a mono- or di-C1-6 alkylamino group (e.g., methylamino, ethylamino, dimethylamino and diethylamino groups, etc.), a C1-6 alkyl-carbonyloxy group (e.g., acetoxy and ethylcarbonyloxy groups, etc.) and a halogen atom (e.g., fluorine, chlorine and bromine atoms, etc.), etc. Especially preferred are optionally-halogenated alkyl groups, for example, C1-6 alkyl groups, and C1-6 alkyl groups substituted by from 1 to 4 or so halogen atoms, etc. Such alkyl groups and halogenated alkyl groups include, for example, methyl, chloromethyl, fluoromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 1-(trifluoromethyl)ethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, 4-trifluoromethylbutyl, hexyl, 6,6,6-trifluorohexyl and 5-trifluoromethylpentyl groups, etc.
More preferably, the xe2x80x9coptionally substituted alkyl groupxe2x80x9d includes optionally halogenated C1-4 alkyl groups, for example, C1-4 alkyl groups and C1-4 alkyl groups substituted by from 1 to 3 or so halogen atoms, etc., such as methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl and tert-butyl groups, etc.
The xe2x80x9coptionally halogenated alkoxy groupxe2x80x9d, which Ring A and Ring B may have, includes, for example, C1-6 alkoxy groups or C1-6 alkoxy groups substituted by from 1 to 5 or so halogen atoms such as those mentioned hereinabove, etc. Such alkoxy groups or halogenated alkoxy groups include, for example, methoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy and hexyloxy groups, etc. Preferably, the xe2x80x9coptionally halogenated alkoxy groupxe2x80x9d includes C1-4 alkoxy groups or C1-4 alkoxy group substituted by from 1 to 3 or so halogen atoms, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy and sec-butoxy groups, etc.
The xe2x80x9coptionally halogenated alkylthio groupxe2x80x9d, which Ring A and Ring B may have, includes, for example, C1-6 alkylthio groups, and C1-6 alkylthio groups having from 1 to 5 or so halogen atoms such as those mentioned hereinabove, etc. Such alkylthio groups and halogenated alkylthio groups include, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio groups, etc. Preferably, the xe2x80x9coptionally halogenated alkylthio groupxe2x80x9d includes C1-4 alkylthio groups, or C1-4 alkylthio groups substituted by from 1 to 3 or so halogen atoms, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio and 4,4,4-trifluorobutylthio groups, etc.
The aryl group as the substituent includes C6-10 aryl groups (e.g., phenyl group, etc.); the acylamino group includes, for example, C1-7 acylamino groups (e.g., formylamino, acetylamino, propionylamino, butyrylamino and benzoylamino groups, etc.), etc. The acyloxy group includes, for example, C1-3 acyloxy groups (e.g., formyloxy, acetoxy and propionyloxy groups, etc.), etc. The mono- or di-alkylamino group includes, for example, mono- or di-C1-4 alkylamino groups (e.g., methylamino, ethylamino, propylamino, dimethylamino and diethylamino groups, etc.), etc. The cyclic amino group includes, for example, 5-membered to 9-membered cyclic amino groups optionally having from 1 to 3 hetero atoms, such as oxygen atom, sulfur atom, etc., in addition to nitrogen atom (e.g., pyrrolidino, piperidino and morpholino groups, etc.), etc. The alkylcarbonylamino group includes, for example, C1-4 alkyl-carbonylamino groups (e.g., acetylamino, propionylamino and butyrylamino groups, etc.); the alkylsulfonylamino group includes, for example, C1-4 alkylsulfonylamino groups (e.g., methylsulfonylamino and ethylsulfonylamino groups, etc.); the alkoxycarbonyl group includes, for example, C1-4 alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl groups, etc.); the alkylcarbonyl group includes, for example, C1-6 alkylcarbonyl groups (e.g., methylcarbonyl, ethylcarbonyl and propylcarbonyl groups, etc.); the mono- or di-alkylcarbamoyl group includes, for example, mono- or di-C1-4 alkylcarbamoyl groups (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and diethylcarbamoyl groups, etc.); the alkylsulfonyl group includes, for example, C1-6 alkylsulfonyl groups (e.g., methylsulfonyl, ethylsulfonyl and propylsulfonyl groups, etc.), etc.
The terminology xe2x80x9coptionally halogenatedxe2x80x9d as referred to herein means that the number of halogen atoms, if substituted, is from 1 to 5, preferably from 1 to 3 or so.
Preferred substituents for the optionally substituted Ring A and Ring B include a halogen atom, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-4 alkoxy group, an optionally halogenated C1-4 alkylthio group, a C1-3 acyloxy group, a hydroxyl group, an amino group, a mono- or di-C1-4 alkylamino group, a carboxyl group, a C14 alkoxycarbonyl group, an oxo group, etc.
More preferred substituents for the optionally substituted Ring A and Ring B include a halogen atom, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-4 alkoxy group, a hydroxyl group, an amino group, a mono- or di-C1-4 alkylamino group, a C1-3 acyloxy group, an oxo group, etc. Especially preferred are a halogen atom, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-4 alkoxy group, etc.
The substituents for Ring A and Ring B, if any, may be at any substitutable position. If the rings are substituted by two or more substituents, the substituents may be the same or different. The number of the substituents may be from 1 to 4 or so, preferably from 1 to 3 or so.
If the Ring A and/or the Ring B has nitrogen atom(s), the ring may form a quaternary salt. For example, it may form a salt with halide ion(s) (e.g., Clxe2x88x92, Brxe2x88x92, Ixe2x88x92, etc.) or other anion(s) such as sulfato ion, hydroxyl ion, etc.
Regarding xe2x80x9cRing Axe2x80x9d
Preferred homocyclic rings for Ring A are optionally substituted homocyclic rings composed of carbon atoms, for example, including those of a formula (A-1):
wherein xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 indicates a single bond or a double bound and the same shall apply hereinunder; and A1 represents a halogen atom (e.g., fluorine and chlorine atoms, etc.), an optionally-halogenated C1-4 alkyl group (e.g., methyl, isopropyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl and pentafluoroethyl groups, etc.), or an optionally halogenated C1-4 alkoxy group (e.g., methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy and pentafluoroethoxy groups, etc.); or those of a formula (A-2):
wherein A2 and A3 are the same or different and represent, independently, a halogen atom (e.g., fluorine and chlorine atoms, etc.), an optionally halogenated C1-4 alkyl group (e.g., methyl, isopropyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl and pentafluoroethyl groups, etc.), or an optionally halogenated C1-4 alkoxy group (e.g., methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-trifluroroethoxy and pentafluoroethoxy groups, etc.).
More preferred homocyclic rings include, for example, benzene rings of a formula (A-3):
wherein A4 and A5 are the same or different and represent, independently, a halogen atom (e.g., fluorine and chlorine atoms, etc.), or an optionally-halogenated C1-4 alkyl group (e.g., methyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and isopropyl groups, etc.).
Also preferred are optionally substituted benzene rings of a formula (A-4):
wherein the symbols have the same meanings as above.
Of the homocyclic rings of the above-mentioned formulae, especially preferred are those as substituted by the following substituent(s):
(1) Homocyclic rings where A1 is a halogen atom (e.g., fluorine and chlorine atoms, etc.), or an optionally-substituted C1-4 alkyl group (e.g., methyl, trifluoromethyl, ethyl and isopropyl groups, etc.).
(2) Homocyclic rings where A2 and A3 are the same or different and represent, independently, an optionally-halogenated C1-4 alkyl group (e.g., methyl, trifluoromethyl, ethyl and isopropyl groups, etc.), or an optionally-halogenated C1-4 alkoxy group (e.g., methoxy, trifluoromethoxy and ethoxy groups, etc.).
(3) Homocyclic rings where A4 and A5 are the same or different and represent, independently, a C1-4 alkyl group (e.g., methyl, ethyl and isopropyl groups, etc.).
(4) Homocyclic rings where A1 is a halogen atom (e.g., fluorine and chlorine atoms, etc.).
(5) Homocyclic rings where A2 and A3 are the same or different and represent, independently, a C1-4 alkoxy group (e.g., methoxy and ethoxy groups, etc.).
Preferred aromatic heterocyclic or non-aromatic heterocyclic rings for Ring A are 5-membered or 6-membered, aromatic heterocyclic or non-aromatic heterocyclic rings including, for example, pyridine, pyrazine, thiophene, tetrahydropyridine, pyrrole and thiazole rings, etc. Concretely, for example, preferred are heterocyclic rings of a formula (A-5):
As preferred examples of optionally substituted aromatic or non-aromatic heterocyclic rings for Ring A, mentioned are pyridine, pyrazine, thiophene, tetrahydropyridine, pyrrole and thiazole rings, etc. optionally having one or two substituents selected from an oxo group, an optionally substituted alkyl group (this has the same meaning as the substituent for the optionally substituted Ring A and Ring B), a C6-10 aryl group (e.g., phenyl group, etc.) and a halogen atom (e.g., fluorine, chlorine and bromine atoms, etc.). Concretely, for example, preferred are aromatic or non-aromatic heterocyclic rings of a formula (A-6):
wherein D1 represents a hydrogen atom, a halogen atom (e.g., fluorine, chlorine and bromine atoms, etc.); E1 represents a C1-4 alkyl group (e.g., methyl, ethyl, propyl and isopropyl groups, etc.); the compounds having the partial structure of (ii) form quaternary ammonium salts along with a halide ion (e.g., Clxe2x88x92, Brxe2x88x92, Ixe2x88x92, etc.), a sulfato ion, a hydroxyl ion or the like; G represents a hydrogen atom or a C1-4 alkyl group (e.g., methyl, ethyl, propyl and isopropyl groups, etc.); J represents a hydrogen atom, a C1-4 alkyl group (e.g., methyl, ethyl, propyl and isopropyl groups, etc.) or a C6-10 aryl group (e.g., phenyl group, etc.).
More preferably, ring A is a pyridine ring which may be substituted by 1 to 3 substituents selected from a halogen atom or C1-4 alkyl group.
Ring A is preferably a 5-membered or a 6-membered, nitrogen-containing heterocyclic ring, for example, (i) a 6-membered, aromatic, nitrogen-containing heterocyclic ring having one or two nitrogen atoms in addition to carbon atoms (e.g., pyridine and pyrazine rings, etc.), (ii) a 6-membered, non-aromatic heterocyclic ring having one or two nitrogen atoms in addition to carbon atoms (e.g., tetrahydropyridine, tetrahydropyrimidine and tetrahydropyridazine rings, etc.), or the like. Especially preferably, Ring A is an aromatic, nitrogen-containing heterocyclic ring, particularly, a pyridine ring or the like.
Regarding xe2x80x9cRing Bxe2x80x9d
Preferred homocyclic rings for Ring B are optionally substituted homocyclic rings composed or carbon atoms, for example, including those of a formula (B-1):
wherein B1 represents a halogen atom, an optionally halogenated C1-4 alkyl group or an optionally halogenated C1-4 alkoxy group; those of a formula (B-2):
wherein B2 and B3 are the same or different and represent, independently, a halogen atom, an optionally halogenated C1-4 alkyl group or an optionally halogenated C1-4 alkoxy group; and those of a formula (B-3):
wherein B4, B5 and B6 are the same or different and represent, independently, a halogen atom, an optionally halogenated C1-4 alkyl group or an optionally halogenated C1-4 alkoxy group.
More preferred are homocyclic rings of a formula (B-4):
wherein B7, B8 and B9 are the same or different and represent, independently, a halogen atom, an optionally halogenated C1-4 alkyl group or an optionally halogenated C1-4 alkoxy group.
Even more preferred are homocyclic rings of a formula (B-5):
wherein B10 represents, a halogen atom, an optionally halogenated C1-4 alkyl group or an optionally halogenated C1-4 alkoxy group.
In the above-mentioned formulae, the halogen atom for any of B1 to B10 includes, for example, fluorine, chlorine and bromine atoms, etc.; the optionally-halogenated C1-4 alkyl group includes, for example, methyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, propyl, 2,2,3,3-tetrafluoropropyl and isopropyl groups, etc.; and the optionally-halogenated C14 alkoxy group includes, for example, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, propoxy, 2,2,3,3-tetrafluoropropoxy and isopropoxy groups, etc.
Ring B is also preferably an optionally substituted benzene ring, which includes, for example, benzene rings of a formula (B-6):
More preferred are benzene rings of a formula (B-7):
Especially preferred are benzene rings of a formula (B-8):
In these formulae, the symbols have the same meanings as above.
Of the substituents in the above-mentioned formulae, for example, especially preferred are the following:
(1) B1, B2, B3, B4, B5 and B6 are the same or different and represent, independently, a halogen atom (e.g., fluorine and chlorine atoms, etc.) or an optionally halogenated C14 alkyl group (e.g., methyl, trifluoromethyl, ethyl and isopropyl groups, etc.).
(2) B1, B2, B3, B4, B5 and B6 are the same or different and represent, independently, an optionally-halogenated C1-4 alkoxy group (e.g., methoxy, trifluoromethoxy and ethoxy groups, etc.).
(3) B7, B8 and B9 represent halogen atoms (e.g., fluorine and chlorine atoms, etc.).
(4) B10 represents a fluorine atom.
(5) B10 represents a C1-4 alkyl group (e.g., methyl group, etc.).
More preferred optionally substituted benzene rings are phenyl groups of a formula (B-9):
As preferred examples of aromatic heterocyclic rings or non-aromatic heterocyclic rings for Ring B, mentioned are 5-membered or 6-membered aromatic heterocyclic rings or non-aromatic heterocyclic rings such as pyridine, thiophene and piperidine rings, etc. These rings may optionally be substituted by substituents such as those mentioned hereinabove as preferred substituents for Ring A.
Where Ring B is an aromatic heterocyclic ring or a non-aromatic heterocyclic ring, it especially preferably includes, for example, heterocyclic rings of a formula (B-10):
Combination of Ring A and Ring B
Where one or both of Ring A and Ring B is/are heterocyclic ring(s), the ring(s) is/are also preferably unsubstituted one(s).
Preferred combinations of Ring A and Ring B (1) are as follows:
(1) One of Ring A and Ring B is a 5-membered or 6-membered heterocyclic ring having one or two hetero atoms selected from nitrogen and sulfur atoms in addition to carbon atoms (e.g., pyridine, pyrazine, thiophene, tetrahydropyridine, piperidine and piperazine rings, etc.) which may be optionally substituted by C1-4 alkyl group(s) (e.g., methyl, ethyl and isopropyl groups, etc.).
One of Ring A and Ring B is a benzene ring optionally substituted by from 1 to 3 substituents selected from a halogen atom (e.g., fluorine, chlorine and bromine atoms, etc.), an optionally halogenated C1-4 alkyl group (e.g., methyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,2-trichloroethyl, propyl and isopropyl groups, etc.) and an optionally halogenated C1-4 alkoxy group (e.g., methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,2-trichloroethoxy, propoxy and isopropoxy groups, etc.).
More preferred combinations of Ring A and Ring B (2) are as follows:
(2) One of Ring A and Ring B is a 5-membered or 6-membered aromatic heterocyclic ring having one or two hetero atoms selected from nitrogen and sulfur atoms in addition to carbon atoms (e.g., pyridine, pyrazine and thiophene rings, etc.).
One of Ring A and Ring B is a benzene ring optionally substituted by from 1 to 3 substituents selected from a halogen atom (e.g., fluorine, chlorine and bromine atoms, etc.), an optionally halogenated C1-4 alkyl group (e.g., methyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl; 2,2,2-trichloroethyl, propyl and isopropyl groups, etc.) and an optionally halogenated C1-4 alkoxy group (e.g., methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,2-trichloroethoxy, propoxy and isopropoxy groups, etc.).
Especially preferably, Ring A is an optionally substituted aromatic heterocyclic ring such as that mentioned above (e.g., an optionally substituted, 5-membered or 6-membered aromatic heterocyclic ring, especially pyridine ring, etc.) while Ring B is an optionally substituted benzene ring.
Regarding xe2x80x9cRing Cxe2x80x9d
In the above-mentioned formulae (I) and (Ia), Ring C represents an optionally substituted homocyclic ring or an optionally substituted heterocyclic ring. The homocyclic ring or the heterocyclic ring may have from 1 to 5 or so, preferably from 1 to 3 or so substituents, which may be the same or different. The substituents may be positioned at any position of the homocyclic or heterocyclic ring.
The homocyclic ring includes xe2x80x9ccyclic hydrocarbon (homocyclic) ringsxe2x80x9d such as those as referred to hereinabove for xe2x80x9cRing A and Ring Bxe2x80x9d, for example, from 3-membered to 10-membered cyclic hydrocarbon rings, preferably 5-membered or 6-membered cyclic hydrocarbon rings, such as benzene, C3-10 cycloalkenes (e.g., cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), C3-10 cycloalkanes (e.g., cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.), etc. Of these, preferred are 6-membered homocyclic rings, such as benzene, cyclohexene and cyclohexane rings, etc. Especially preferred is benzene ring.
The substituents for the above-mentioned benzene ring and other homocyclic rings include, for example, a halogen atom (e.g., fluorine, chlorine, bromine and iodine atoms), an optionally-halogenated C1-10 alkyl group (e.g., methyl, chloromethyl, difluoromethyl trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, 3,3,3-trifluoropropyl, butyl, isobutyl, t-butyl, perfluorobutyl, pentyl, hexyl, octyl and decyl groups, etc.), an amino-substituted C1-4 alkyl group (e.g., aminomethyl and 2-aminoethyl groups, etc.), a mono- or di-C1-4 alkylamino-substituted C1-4 alkyl group (e.g., methylaminomethyl, dimethylaminomethyl, 2-aminoethyl and 2-dimethylaminoethyl groups, etc.), a carboxyl-substituted C1-4 alkyl group (e.g., carboxymethyl and carboxyethyl groups, etc.), a C1-4 alkoxy-carbonyl-substituted C1-4 alkyl group (e.g., methoxycarbonylethyl and ethoxycarbonylethyl groups, etc.), a hydroxyl-substituted C1-4 alkyl group (e.g., hydroxymethyl and hydroxyethyl groups, etc.), a C1-4 alkoxy-carbonyl-substituted C1-4 alkyl group (e.g., methoxymethyl, ethoxyethyl and ethoxyethyl groups, etc.), a C3-10 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups, etc.), a nitro group, a cyano group, a hydroxyl group, an optionally-halogenated C1-10 alkoxy group (e.g., methoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, perfluorobutoxy, pentyloxy, hexyloxy, octyloxy and decyloxy groups, etc.), an optionally-halogenated Cl4 alkylthio group (e.g., methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio and butylthio groups, etc.), an amino group, a mono- or di-C1-4 alkylamino group (e.g., methylamino, ethylamino, propylamino, dimethylamino and diethylamino groups, etc.), a cyclic amino group (e.g., a 5-membered to 9-membered cyclic amino group optionally having from 1 to 3 hetero atoms such as oxygen and sulfur atoms, etc., in addition to nitrogen atoms, concretely for example, pyrrolidino, piperidino and morpholino groups, etc.), a C1-4 alkyl-carbonylamino group (e.g., acetylamino, propionylamino and butyrylamino groups, etc.), an aminocarbonyloxy group, a mono- or di-C1-4 alkylaminocarbonyloxy group (e.g., methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy and diethylaminocarbonyloxy groups, etc.), a C1-4 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino and propylsulfonylamino groups, etc.), a C1-4 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and isobutoxycarbonyl groups, etc.), an aralkyloxycarbonyl group (e.g., benzyloxycarbonyl group, etc.), a carboxyl group, a C1-6 alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl and butylcarbonyl groups, etc.), a C3-6 cycloalkyl-carbonyl group (e.g., cyclohexylcarbonyl group, etc.), a carbamoyl group, a mono- or di-C1-4 alkylcarbamoyl group (e.g., methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl and dibutylcarbamoyl groups, etc.), a C1-6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl and propylsulfonyl groups, etc.), etc.
The homocyclic Ring C may optionally be substituted, for example, by one 5-membered or 6-membered, aromatic monocyclic heterocyclic group (e.g., furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl groups, etc.), etc., and the aromatic monocyclic heterocyclic group may optionally be substituted by from 1 to 3 or so optionally halogenated C1-4 alkyl groups (e.g. , methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl and isopropyl groups, etc.), etc.
As preferred substituents for the homocyclic Ring C (e.g., benzene ring, etc.), for example, mentioned are a halogen atom (e.g., fluorine, chlorine and bromine atoms, etc.), an optionally halogenated C1-6 alkyl group (e.g., methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, 3,3,3-trifluoropropyl, butyl, s-butyl, t-butyl and perfluorobutyl groups, etc.), a nitro group, a hydroxyl group, an optionally halogenated C1-6 alkoxy group (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, 3,3,3-trifluoropropoxy and butoxy groups, etc.), an amino group, a mono- or di-C1-4 alkylamino-substituted C1-4 alkyl group (e.g., methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl and 2-dimethylaminoethyl groups, etc.), a mono- or di-C1-4 alklamino group (e.g., methylamino, ethylamino, dimethylamino and diethylamino groups, etc.), a C1-4 alkoxy-carbonyl group (e.g., methoxycarbonyl and ethoxycarbonyl groups, etc.), a carboxyl group, a carbamoyl group, etc.
More preferred are a halogen atom (e.g., fluorine, chlorine and bromine atoms, etc.), an optionally halogenated C1-4 alkyl group (e.g., methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl and t-butyl groups, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, trifluoromethoxy, ethoxy, 2,2,2-trichloroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy and propoxy groups, etc.), a di-C1-4 alkylamino group (e.g., dimethylamino and diethylamino groups, etc.), a C1-3 acyloxy group (e.g., acetoxy group, etc.), a hydroxyl group, etc. Preferably, the number of the substituents is, for example, from 1 to 3 or so.
Especially, preferred are a halogen atom (e.g., fluorine, chlorine and bromine atoms, etc.), an optionally halogenated C1-4 alkyl group (e.g., methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl and t-butyl groups, etc.), an optionally halogenated C1-4 alkoxy group (e.g., methoxy, trifluoromethoxy, ethoxy, 2,2,2-trichloroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy and propoxy groups, etc.)
The xe2x80x9cheterocyclic ringxe2x80x9d of the xe2x80x9coptionally substituted heterocyclic ringxe2x80x9d includes, for example, from 5-membered to 10-membered heterocyclic rings having from 1 to 4 hetero atoms of the same type or different two types, such as nitrogen, oxygen and/or sulfur atoms, etc., in addition to carbon atoms, etc. Concretely, the heterocyclic ring includes, for example;
(1) 5-membered or 6-membered, aromatic monocyclic heterocyclic rings, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.;
(2) 9-membered or 10-membered, aromatic, condensed heterocyclic rings, such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indoliyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, a-carbolinyl, xcex2-carbolinyl, g-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[l;5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a)pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.;
(3) from 5-membered to 10-membered, non-aromatic heterocyclic rings, such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, pyrazinyl, etc.
Of the above-mentioned heterocyclic rings (1) to (3), for example, 5-membered or 6-membered heterocyclic rings having from 1 to 3 hetero atoms, such as nitrogen, oxygen and sulfur atoms, etc., in addition to carbon atoms, are widely utilized. Such heterocyclic rings include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, thiazolyl, thiadiazolyl, thiophenyl, etc.
As the substituents for the optionally substituted heterocyclic rings, mentioned are substituents such as those as referred to hereinabove for the foregoing xe2x80x9coptionally substituted homocyclic ringsxe2x80x9d.
More preferably, Ring C includes optionally substituted benzene rings (especially, substituted benzene rings), for example, benzene rings optionally substituted by from 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-4 alkyl group, an optionally substituted C1-4 alkoxy group, a di-C1-4 alkylamino group, a C1-3 acyloxy group and a hydroxyl group (especially, benzene rings substituted by such substituent(s)). Concretely, the preferred Ring C includes, for example, optionally substituted benzene rings of a formula (C-1):
wherein C1, C2 and C3 are the same or different and represent, independently, a hydrogen atom, a halogen atom, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-4 alkoxy group, a mono- or di-C1-4 alkylamino group, a C1-3 acyloxy group or a hydroxyl group; and
optionally substituted benzene rings of a formula (C-2):
wherein C4 and C5 are the same or different and represent, independently, a hydrogen atom, a halogen atom, an optionally halogenated C1-4 alkyl group or an optionally halogenated C1-4 alkoxy group.
The halogen atom, the optionally halogenated C1-4 alkyl group, the optionally halogenated C1-4 alkoxy group and the mono- or di-C1-4 alkylamino group to be represented by any of C1, C2, C3, C4 and C5 may be the same as the above-mentioned halogen atom, optionally halogenated C1-4 alkyl group, optionally halogenated C1-4 alkoxy group and mono- or di-C1-4 alkylamino group, respectively.
Even more preferably, Ring C includes, for example, benzene rings of the above-mentioned formulae (C-1) and (C-2) where C1 to C5 are as follows:
(1) C1, C2 and C3 are the same or different and represent, independently, a halogen atom, an optionally halogenated C1-4 alkyl group or an optionally halogenated C1-4 alkoxy group;
(2) C1, C2 and C3 are the same or different and represent, independently, a halogen atom or an optionally halogenated C1-4 alkyl group;
(3) C1, C2 and C3 are the same or different and represent, independently, a halogen atom;
(4) C1, C2 and C3 are the same or different and represent, independently, an optionally halogenated C1-4 alkyl group;
(5) C1, C2 and C3 are the same or different and represent, independently, an optionally halogenated C1-4 alkoxy group;
(6) C4 and C5 are the same or different and represent, independently, a halogen atom;
(7) C4 and C5 are the same or different and represent, independently, an optionally halogenated C1-4 alkyl group; or
(8) C4 and C5 are the same or different and represent, independently, an optionally halogenated C1-4 alkoxy group.
As examples of the xe2x80x9coptionally halogenated C1-4 alkyl groupxe2x80x9d, the xe2x80x9coptionally halogenated C1-4 alkoxy groupxe2x80x9d and the xe2x80x9chalogen atomxe2x80x9d in the above-mentioned embodiments (1) to (8), referred to are the same ones as those mentioned hereinabove.
Further more preferably, Ring C includes, for example, benzene rings of the above-mentioned formula (C-2) where C4 and C5 are as follows:
(a) one of C4 and C5 is a hydrogen atom and the other is a methoxy group;
(b) C4 and C5 are both chlorine atoms;
(c) one of C4 and C5 is a methoxy group and the other is an isopropyl group;
(d) one of C4 and C5 is a methoxy group and the other is a 1-methoxy-1-methylethyl group; or
(e) C4 and C5 are both trifluoromethyl groups.
Regarding xe2x80x9cRing Zxe2x80x9d
In the above-mentioned formulae, Ring Z represents an optionally-substituted nitrogen containing heterocyclic ring. Various substituents are referred to as substituents for Ring Z, which include, for example, an alkyl group (e.g., a linear or branched alkyl group having from 1 to 6 carbon atoms, preferably a linear or branched alkyl group having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups, etc.), an alkenyl group (e.g., an alkenyl group having from 2 to 6 carbon atoms, preferably an alkenyl group having from 2 to 4 carbon atoms, such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl sec-butenyl groups, etc.), an alkynyl group (e.g., an alkynyl group having from 2 to 6 carbon atoms, preferably an alkynyl group having from 2 to 4 carbon atoms, such as ethynyl, propynyl, isopropynyl, butynyl, isobutynyl and sec-butynyl groups, etc.), a cycloalkyl group (e.g., a C3-8 cycloalkyl group, preferably a C3-6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, etc.), a cycloalkyl-alkyl group (e.g., a C3-6 cycloalkyl-Cl4 alkyl group, such as cyclopropylmethyl, cyclopropylethyl and cyclohexylmethyl groups, etc.), an aryl group (e.g., an aryl group having from 6 to 14 carbon atoms, preferably an aryl group having from 6 to 10 carbon atoms, such as phenyl, 1-naphthyl, 2-naphthyl, anthryl and phenanthryl groups, etc., especially, phenyl group), a nitro group, a cyano group, a hydroxyl group, a C1-4 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy and butoxy groups, etc.), a C1-4 alkylthio group (e.g., methylthio, ethylthio and propylthio groups, etc.), an amino group, a mono- or di-C1-4 alkylamino group (e.g., methylamino, ethylamino, propylamino, dimethylamino and diethylamino groups, etc.), a cyclic amino group (e.g., a 5-membered to 9-membered cyclic amino group optionally having from 1 to 3 hetero atoms, such as oxygen and sulfur atoms, etc., in addition to nitrogen atom, concretely, for example, pyrrolidino, piperidino, morpholino and thiomorpholino groups, etc.), a C1-4 alkyl-carbonylamino group (e.g., acetylamino, propionylamino and butyrylamino groups, etc.), a C1-4 alkylsulfonylamino group (e.g., methylsulfonylamino and ethylsulfonylamino groups, etc.), a C1-4 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl groups, etc.), a carboxyl group, a C1-6 alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl and propylcarbonyl groups, etc.), a carbamoyl group, a mono- or di-C1-4 alkylcarbamoyl group (e.g., methylcarbamoyl and ethylcarbamoyl groups, etc.), a C1-6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl and propylsulfonyl groups, etc.), an oxo group, a thioxo group, etc. The number of the substituents is, for example, from 1 to 5 or so, preferably 1, 2 or so, depending on the size of Ring Z.
Ring Z may be a heterocyclic ring optionally having at least one hetero atom selected from nitrogen, oxygen and sulfur atoms, in addition to Y and the nitrogen atom N, and is preferably an optionally oxoated ring.
Ring Z includes rings of a formula (Z-1):
wherein D and E represent groups from which Ring Z as mentioned above is formed via the nitrogen atom adjacent to E.
Preferably, D and E which form Ring Z represent, independently, an alkylene group optionally having an oxo group, oxyalkylene group, or iminoalkylene group. The alkylene groups optionally having an oxo group to be represented by D and E preferably have carbon atoms from which Ring Z is formed to be a 5-membered to 12-membered ring, preferably a 5-membered to 9-membered ring. The numbers of the carbon atoms that constitute the alkylene groups of D and E may be the same or different.
Preferably, D includes, for example, C1-7 alkylene group optionally having an oxo group, especially C1-5 alkylene group optionally having an oxo group C1-7 oxyalkylene groups, especially C1-5 oxyalkylene groups, C1-7 iminoalkylene groups, especially C1-5 imminoalkylene groups. More preferably, D includes an alkylene group of a formula xe2x80x94(CH2)mxe2x80x94 (where m is from 1 to 7), an oxyalkylene group of a formula xe2x80x94Oxe2x80x94(CH2)p (where p is from 1 to 7), iminoalkylene group of a formula xe2x80x94NHxe2x80x94(CH2)q (where q is from 1 to 7. In these formula, m is preferably from 1 to 5, more preferably from 2 to 5.
Preferably, E includes, for example, C1-3 alkylene group optionally having an oxo group, more preferably an alkylene group optionally having an oxo group having one or two carbon atoms, even more preferably a methylene group optionally having an oxo group.
The number of the oxo groups that are substitutable in Ring Z is not specifically limited but may be selected from 1 to 3 or so depending on the size of Ring Z. Where Ring Z is a 5-membered to 10-membered ring, the number of the substitutable oxo groups is 1, 2 or so. Oxo group(s) may be substituted at at least either one of D and/or E. Preferably, oxo group(s) is/are substituted at E in Ring Z.
Preferably, in Ring Z, D is an alkylene group or oxyalkylene group having from 1 to 5 carbon atoms, more preferably from 2 to 5 carbon atoms especially, an alkylene group having from 2 to 5 carbon atoms, while E is an alkylene group having an oxo group having 1 or 2 carbon atoms, especially  greater than Cxe2x95x90O. Especially preferably, Ring Z includes, for example, from 5-membered to 9-membered rings of a formula (Z-2):
wherein each m and p, independently, represents an integer of from 1 to 5.
Regarding xe2x80x9cnxe2x80x9d
In the above-mentioned formulae, n represents an integer of from 1 to 6, preferably an integer of from 1 to 3, especially preferably 1 or 2. More preferably, n is 1.
Regarding Compounds (I) and (Ia)
In compounds of the above-mentioned general formulae (I) and (Ia), the combination of xe2x80x9cRing Mxe2x80x9d xe2x80x9cxe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than xe2x80x9d, xe2x80x9cRaxe2x80x9d, xe2x80x9cRbxe2x80x9d, xe2x80x9cRing Axe2x80x9d, xe2x80x9cRing Bxe2x80x9d, xe2x80x9cRing Cxe2x80x9d, xe2x80x9cRing Zxe2x80x9d and xe2x80x9cnxe2x80x9d is not specifically limited. These may be combined suitably to construct the compounds (I) and (Ia). Preferred compounds (I) and (Ia) are constructed by combining the above-mentioned preferred embodiments of xe2x80x9cRing Mxe2x80x9d xe2x80x9cX{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than xe2x80x9d, xe2x80x9cRaxe2x80x9d, xe2x80x9cRbxe2x80x9d, xe2x80x9cRing Axe2x80x9d, xe2x80x9cRing Bxe2x80x9d, xe2x80x9cRing Cxe2x80x9d, xe2x80x9cRing Zxe2x80x9d and xe2x80x9cnxe2x80x9d.
Of compounds of the above-mentioned general formula (I), especially those of the above-mentioned general formula (Ia), preferred are (1) the following compounds or pharmaceutically-acceptable salts thereof.
Compounds of formula (I) or (Ia) wherein;
one of Ring A and Ring B is a 5-membered or 6-membered heterocyclic ring having one or two hetero atoms selected from nitrogen and oxygen atoms, in addition to carbon atoms, while the other is a benzene ring, and the Rings A and B may optionally have one or two substituents selected from a halogen atom and an optionally halogenated C1-4 alkyl group;
Ring C is a benzene ring optionally having from 1 to 3 substituents selected from a halogen atom, an optionally halogenated C16 alkyl group (preferably, C1-4 alkyl group) and an optionally halogenated C1-6 alkoxy group (preferably, C1-4 alkoxy group);
D that constitutes Ring Z is xe2x80x94(CH2)mxe2x80x94 (where m is an integer of from 1 to 7) or xe2x80x94Oxe2x80x94(CH2)pxe2x80x94 (where p is an integer of from 1 to 7);
E that constitutes Ring Z is  greater than Cxe2x95x90O;
xe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than  is xe2x80x94COxe2x80x94N less than ;
n is 1,
or pharmaceutically-acceptable salts thereof.
The above-mentioned xe2x80x9c5-membered or 6-membered heterocyclic ringxe2x80x9d includes, for example, pyridine, pyrazine, pyrrole, thiophene, thiazole, tetrahydropyrazine, piperidine, etc. Concretely, Ring A includes heterocyclic rings of the above-mentioned formula (A-5), etc., and Ring B includes benzene rings of the above-mentioned formulae (B-7) and (B-8), especially the above-mentioned formula (B-10), etc.
The above-mentioned xe2x80x9chalogen atomxe2x80x9d includes, for example, fluorine, chlorine and bromine atoms, etc.; the xe2x80x9coptionally-halogenated C1-4, alkyl groupxe2x80x9d includes, for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl and tert-butyl groups, etc.; the xe2x80x9coptionally halogenated C1-6 alkyl groupxe2x80x9d includes pentyl and hexyl groups, etc., in addition to the above-mentioned alkyl groups and halogenated alkyl groups.
The xe2x80x9coptionally halogenated C1-4 alkoxy groupxe2x80x9d includes, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy and tert-butoxy groups, etc.; and the xe2x80x9coptionally halogenated C1-6 alkoxy groupxe2x80x9d includes pentyloxy and hexyloxy groups, etc., in addition to the above-mentioned alkoxy groups and halogenated alkoxy groups.
Of compounds of the above-mentioned general formula (I), especially those of the above-mentioned general formula (Ia), also preferred are (2) the following compounds or pharmaceutically-acceptable salts thereof.
Compounds of formula (I) or (Ia) wherein;
Ring A is a 5-membered or 6-membered heterocyclic ring having one nitrogen atom or one sulfur atom, in addition to carbon atoms, for example, a heterocyclic ring of a formula (A-7):
Ring B is a benzene ring optionally having from 1 to 3 substituents selected from a halogen atom and an optionally halogenated C1-4 alkyl group;
Ring C is a benzene ring optionally having from 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-4 alkyl group and an optionally halogenated C1-4 alkoxy group;
D that constitutes Ring Z is xe2x80x94(CH2)mxe2x80x94 (where m is an integer of from 1 to 7) or xe2x80x94Oxe2x80x94(CH2)pxe2x80x94 (where p is integer of from 1 to 7);
E that constitutes Ring Z is  greater than Cxe2x95x90O;
xe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than  is xe2x80x94COxe2x80x94N less than ;
n is 1,
or pharmaceutically-acceptable salts thereof.
As examples of the xe2x80x9chalogen atomxe2x80x9d, the xe2x80x9coptionally halogenated C1-4 alkyl groupxe2x80x9d and the xe2x80x9coptionally halogenated C1-4 alkoxy groupxe2x80x9d, mentioned are those as referred to hereinabove for the foregoing compounds (1).
More preferably, compounds of formula (I) or (Ia) wherein; Ra and Rb are the same or different and represent, independently, a hydrogen atom, optionally halogenated C1-4 alkyl groups, C1-6 alkoxy-C1-6 alkyl groups, C1-6 alkylthio-C1-6 alkyl groups, amino-C1-6 alkyl groups, C1-7 acylamino-C1-6 alkyl groups, mono- or di-C1-6 alkylamino-C1-4 alkyl groups, C3-10 cycloalkylamino-C1-6 alkyl groups, C1-6 alkyl groups having 5-membered or 6-membered cyclioamino which optionally substituted by C1-6 alkyl, C1-6 alkylsulfonylamino-C1-6 alkyl or C1-6 alkylcarbonyloxy-C1-6 alkyl; or
Ra and Rb are bonded to each other to form pyridine ring which is optionally substituted by 1 to 3 substituents selected from a halogen atom and a C1-4 alkyl group;
Ring B is a benzene ring optionally having 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-4 alkyl group and an optionally halogenated C1-4 alkoxy group;
Ring C is a benzene ring optionally having 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-4 alkyl group, an optionally halogenated C1-4 alkoxy group, an amino group optionally substituted by C1-4 alkyl group, a C1-3 acyloxy group and a hydroxyl group;
Ring Z is a 5-membered to 10-membered nitrogen containing heterocyclic ring optionally having an oxo group and optionally substituted C1-4 alkyl group or a hydroxy group;
xe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Yxe2x80x94 is xe2x80x94Nxe2x95x90C less than  or xe2x80x94COxe2x80x94N less than  and n is an integer of 1;
and n is 1, or pharmaceutically-acceptable salts thereof.
Preferred compounds of formulae (I) and (Ia) include, for example, compounds of the following general formula or salts thereof.
wherein D and E represent alkylene groups, optionally having an oxo group and the other symbols have the same meanings as above.
Preferably, D and E represent, independently, a C1-3 alkylene group optionally substituted by one oxo group.
More preferred compounds of formulae (I) and (Ia) include, for example, compounds of the following general formula or salts thereof.
wherein m represents an integer of from 1 to 7, and the other symbols have the same meanings as above.
m is preferably an integer of from 2 to 5.
Where the above-mentioned compounds of formulae (I) and (Ia) form salts and used in medicines, it is preferable that the salts are pharmaceutically-acceptable salts.
Examples of such pharmaceutically-acceptable salts include salts with inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, nitric acid, etc., or salts with organic acids, such as acetic acid, malic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, palmitic acid, salicylic acid, stearic acid, etc.
Compounds (I) and (Ia) or salts thereof of the present invention include stereoisomers such as cis- and trans-isomers, etc., racemates, as well as optically-active forms such as R-forms, S-forms, etc. Depending on the size of Ring Z, compounds (I) and (Ia) or salts thereof may include conformation-dependent isomers. All such isomers are within the scope of the compounds (I) and (Ia) or salts thereof of the present invention.
Method for Producing Compounds or Salts Thereof
Compounds (I) and (Ia) or salts thereof of the present invention can be produced, for example, by cyclizing a compound of the following general formula (II) or a salt thereof.
wherein L represents a leaving group, and the other symbols have the same meanings as above.
The leaving group L in compound (II) includes, for example, a halogen atom (e.g., chlorine, bromine and iodine atoms, etc.), a substituted sulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy and p-toluenesulfonyloxy groups, etc.), etc.
The compound (II) can be applied to the reaction as a free compound but may also be applied thereto as its salt (for example, as an alkali metal salt, such as lithium, sodium, potassium or the like salt, of the compound). In general, the reaction is conducted in a solvent that is inert to the reaction. As the solvent, for example, preferably used is any of halogenated hydrocarbons such as dichloromethane, chloroform, etc., nitriles such as acetonitrile, etc., ethers such as dimethoxyethane, tetrahydrofuran, etc., aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc.
Addition of a base to the reaction system advantageously promotes the reaction. As the base, for example, advantageously employed is any of inorganic bases (alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; alkali metal hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; sodium amide; alkoxides such as sodium methoxide, sodium ethoxide, etc.), and organic bases (amines such as trimethylamine, triethylamine, diisopropylethylamine, etc.; cyclic amines such as pyridine, etc.).
In the above-mentioned cyclization, it is also possible to convert the compound (II) into its salt with a base (for example, any of the above-mentioned alkali metal salts, alkaline earth metal salts, etc.) prior to the reaction, in place of using the base. The amount of the base, if used, varies, depending on the kind of the compound (II) and the solvent to be used and on the other reaction conditions, and is, in general, from 1 to 10 mols or so, preferably from 1 to 5 mols or so, per mol of the compound (II) used.
The reaction temperature falls, for example, within the range between about xe2x88x9250xc2x0 C. and about 200xc2x0 C., preferably between about xe2x88x9220xc2x0 C. and about 150xc2x0 C. The reaction time varies, depending on the kind of the compound (II) used or the kind of its salt used and also on the reaction temperature, etc., and is, for example, from 1 to 72 hours or so, preferably from 1 to 24 hours or so.
Of compounds (I) and (Ia) of the present invention, those where Ring A is a tetrahydropyridine ring can be produced by reducing compounds (I) and (Ia) where Ring A is a pyridine ring. The reduction can be conducted by various methods. For example, preferred is a method of reducing the compounds in the presence of a metal catalyst for catalytic reduction. The catalyst to be employed in the catalytic reduction includes, for example, platinum catalysts such as platinum black, platinum oxide, platinum carbon, etc., palladium catalysts such as palladium black, palladium oxide, palladium barium sulfate, palladium carbon, etc.; nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, Urushibara nickel, etc. The amount of the catalyst to be used varies, depending on the type of the catalyst, and is, in general, from 0.1 to 10% (w/w) or so relative to the compound (I) or (Ia) to be reduced.
The reduction is generally conducted in a solvent. The solvent includes, for example, alcohols such as methanol, ethanol, propanol, isopropanol, etc., ethers such as tetrahydrofuran, dioxane, etc., esters such as ethyl acetate, etc. The reaction temperature falls, for example, between 0xc2x0 C. and 200xc2x0 C. or so, preferably between 20xc2x0 C. and 110xc2x0 C. or so. The reaction time is generally from 0.5 to 48 hours or so, preferably from 1 to 16 hours or so. In general, the reaction is conducted under normal pressure in many cases but, if desired, may be conducted under pressure (for example, at from 3 to 10 atmospheres or so).
The reduction may also apply to the conversion of other aromatic heterocyclic rings into non-aromatic heterocyclic rings.
Compounds of formulae (I) and (Ia) where Ring A is a tetrahydropyridine ring can also be produced by reacting a compound of formula (I) or (Ia) where Ring A is a pyridine ring with an alkylating agent of a formula, Q-Lxe2x80x2 (where Q represents an optionally substituted alkyl group, and Lxe2x80x2 represents a removable group) to convert it into the corresponding quaternary salt, followed by reducing the resulting quaternary salt. As examples of the removable group Lxe2x80x2, referred to are those of the removable group L as mentioned hereinabove.
The alkylating agent Q-Lxe2x80x2 that is used for converting the compound into the corresponding quaternary salt includes alkane halides (e.g., chlorides, bromides, iodides, etc.), sulfates and sulfonates (e.g., methanesulfonates, p-toluenesulfonates, benzenesulfonate, etc.), etc. Especially preferred are alkyl halides. The amount of the alkylating agent to be used is, for example, from 1 to 100 equivalents or so, preferably from 1 to 30 equivalents or so, per mol of the substrate.
The alkylation is generally conducted in a solvent. The solvent includes, for example, alcohols such as methanol, ethanol, propanol, isopropanol, etc., ethers such as tetrahydrofuran, dioxane, etc., esters such as ethyl acetate, etc., halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, etc. It is also possible to use the alkylating agent itself as the solvent. The reaction temperature falls, for example, between 10xc2x0 C. and 200xc2x0 C. or so, preferably between 20xc2x0 C. and 110xc2x0 C. or so. The reaction time is generally from 0.5 to 24 hours or so, preferably from 1 to 16 hours or so.
The reduction of the quaternary salt as formed in the previous reaction into a tetrahydropyridine ring may be conducted in the presence of a reducing agent, such as a metal hydride or the like, in an inert solvent. The metal hydride to be used as the reducing agent includes, for example, sodium borohydride, lithium borohydride, zinc borohydride, sodium borocyanohydride, lithium borocyanohydride, lithium aluminium hydride, etc. Of these, preferred are sodium borohydride, etc. The amount of the reducing agent to be used is, for example, from 1 to 10 equivalents or so, preferably from 1 to 2 equivalents or so, relative to the quaternary salt. The reaction solvent includes, for example, lower alcohols such as methanol, ethanol, etc., ethers such as dioxane, tetrahydrofuran, etc., hydrocarbons such as benzene, toluene, etc. These solvents can be used singly or as combined. The reaction temperature falls, in general, between about xe2x88x92100xc2x0 C. and about 40xc2x0 C., preferably between about xe2x88x9280xc2x0 C. and about 25xc2x0 C. The reaction time is generally from 5 minutes to 10 hours or so, preferably from 10 minutes to 5 hours or so.
As the case may be, the reduction of the above-mentioned quaternary salts may give compounds of the present invention having a dihydropyridine ring, depending on the type of the quaternary salts to be reduced. The dihydropyridine ring thus formed may further be reduced into a tetrahydropyridine ring, for example, according to the above-mentioned catalytic reduction or the like. Where Ring A is a tetrahydropyridine ring and its nitrogen atom has a hydrogen atom as bonded thereto, it may be alkylated with the above-mentioned alkylating agent of formula Q-Lxe2x80x2 (where the symbols have the same meanings as above) to thereby introduce the group Q into the nitrogen atom of the ring. In this manner, therefore, compounds of the invention where the nitrogen atom of the tetrahydropyridine Ring A is substituted by the group Q are obtained.
It is also possible to obtain compounds of the invention where Ring A is a pyridone ring by oxidizing the corresponding compounds where Ring A is a quaternary salt of a pyridine ring. The oxidation can be conducted, for example, in accordance with a known method (see E. A. Prill et al.; Organic Syntheses, Combined Vol. 2. p. 419 (1957)) or with reference thereto.
Compounds of the invention where Ring B is an aromatic heterocyclic ring can be converted into the corresponding compounds where Ring B is a non-aromatic heterocyclic ring by reducing them in the same manner as above.
Of compounds (I) of the present invention, those where xe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than  is xe2x80x94CSxe2x80x94N less than  can be produced by reacting the corresponding compounds where xe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than  is xe2x80x94COxe2x80x94N less than  with a suitable sulfide. The sulfide includes, for example, phosphorus pentasulfide, Lowesson reagents, etc. This reaction is, in general, conducted in the absence of water in a solvent, for example in a halogenated hydrocarbon such as dichloromethane, chloroform or the like, an ether such as dioxane, tetrahydrofuran or the like, or a hydrocarbon such as benzene, toluene or the like. The amount of the sulfide to be used is not smaller than the equimolar amount, preferably from 2 to 5 mols or so, relative to the compound to be sulfidized therewith. The reaction temperature falls, for example, between 20xc2x0 C. and 120xc2x0 C. or so. The reaction time varies, depending on the kind of the compound to be sulfidized, the type of the sulfide to be used, the reaction temperature, etc., and is, for example, from 1 to 8 hours or so.
Where the compounds (I) and (Ia) or salts thereof which are produced according to the methods mentioned above have lower (C1-6) alkoxy group(s) at the benzene ring(s) in the groups of Ring A, Ring B and Ring C, if desired, these may optionally be reacted with, for example, boron tribromide or the like according to known methods to thereby convert the lower alkoxy group(s) into hydroxyl group(s). This reaction may be conducted, in general, in a solvent (e.g., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, etc., hydrocarbons such as benzene, toluene, etc.), at from about xe2x88x9220xc2x0 C. to about 80xc2x0 C., preferably at from about 0xc2x0 C. to about 30xc2x0 C. The amount of boron tribromide to be used is from about 1 to about 10 molar equivalents, preferably from about 1 to about 5 molar equivalents, relative to one lower alkoxy group. The reaction time is, in general, from 15 minutes to 24 hours or so, preferably from 30 minutes to 12 hours or so.
Where the compounds (I) and (Ia) or salts thereof which are produced according to the methods mentioned above have hydroxyl group(s) at the benzene ring(s) in the groups of Ring A, Ring B and ring C, if desired, these may be alkylated or acylated to thereby convert the hydroxyl group(s) into alkoxy or acyloxy group(s).
The alkylation may be conducted in the presence of a base in a solvent by making the compounds reacted with an alkylating agent. The solvent includes, for example, alcohols such as methanol, ethanol, propanol, etc., ethers such as dimethoxyethane, dioxane, tetrahydrofuran, etc., ketones such as acetone, etc., amides such as N,N-dimethylformamide, etc. The base includes, for example, organic bases such as trimethylamine, triethylamine, N-methylmorpholine, pyridine, picoline, N,N-dimethylaniline, etc., and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, etc. The alkylating agent includes, for example, optionally substituted alkane halides (e.g., chlorides, bromides, iodides, etc.), sulfates and sulfonates (e.g., methanesulfonates, p-toluenesulfonates, benzenesulfonates, etc.), etc. The amount of the alkylating agent to be used is from about 1 to about 5 molar equivalents, preferably from about 1 to about 3 molar equivalents, relative to mol of the starting phenolic derivative. The reaction temperature falls, in general, between about xe2x88x9210xc2x0 C. and about 100xc2x0 C., preferably from about 0xc2x0 C. and about 80xc2x0 C. The reaction time is, in general, from 15 minutes to 24 hours or so, preferably from 30 minutes to 12 hours or so.
The acylation is conducted by reacting the phenolic derivative with a desired carboxylic acid or a reactive derivative thereof. This reaction is generally conducted in a solvent, though depending on the type of the acylating agent to be used and the kind of the starting phenolic derivative to be acylated. If desired, a base may be added to the reaction system so as to promote the reaction. The solvent includes, for example, hydrocarbons such as benzene, toluene, etc., ethers such as ethyl ether, dioxane, tetrahydrofuran, etc., esters such as ethyl acetate, etc., halogenated hydrocarbons such as chloroform, dichloromethane, etc., amides such as N,N-dimethylformamide, etc., aromatic amines such as pyridine, etc. The base includes, for example, hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate, etc., carbonates such as sodium carbonate, potassium carbonate, etc., acetates such as sodium acetate, etc., tertiary amines such as triethylamine, etc., aromatic amines such as pyridine, etc. The reactive derivative of a carboxylic acid, which is used as the acylating agent, includes, for example, acid anhydrides, mixed acid anhydrides, acid halides (e.g., chlorides, bromides), etc. The amount of the acylating agent to be used is from 1 to 5 molar equivalents, preferably from 1 to 3 molar equivalents, relative to mol of the starting phenolic derivative. The reaction temperature falls, in general, between 0xc2x0 C. and 150xc2x0 C. or so, preferably about 10xc2x0 C. and 100xc2x0 C. or so. The reaction time is generally from 15 minutes to 12 hours or so, preferably from 30 minutes to 6 hours or so.
Of compounds of formula (I) and (Ia), those where D is a carbonyl group, an oxyalkylene group [xe2x80x94Oxe2x80x94(CH2)qxe2x80x94] or an iminoalkylene group [xe2x80x94NHxe2x80x94(CH2)qxe2x80x94] can be obtained by reacting the leaving group La (for example, the above-mentioned removable group L such as a halogen atom or the like, an amido group optionally having a substituent at its nitrogen atom, etc.) as substituted on the Ring M in the absence of D with the reactive moiety (for example, the active hydrogen atom of a hydroxyl group, an amino group, a mono-C1-6 alkylamino group or the like) of the substituent as bonded to the nitrogen atom adjacent to E, in accordance with the methods mentioned above. The substituent as bonded to the nitrogen atom adjacent to E is, for example, a linear or branched C1-6 alkylene group optionally having substituent(s) selected from a C1-6 alkyl group, a hydroxyl group, a C1-6 alkoxy group, etc.
Where the compounds (I) and (Ia) are obtained in the above-mentioned methods as free compounds, they can be converted into their salts by ordinary methods, for example, into their salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), organic acids (e.g., methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.), inorganic bases (e.g., alkali metals such as sodium, potassium, etc., alkaline earth metals such as calcium, magnesium, etc., aluminium, ammonium, etc.), organic bases (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine, etc.), etc. Where the compounds (I) are obtained in the form of their salts, the salts may be converted into free compounds or other salts by ordinary methods.
The final compounds (I) and (Ia) or salts thereof thus produced according to the methods mentioned hereinabove can be separated and isolated by ordinary separation and isolation means (for example, by condensation, solvent extraction, column chromatography, recrystallization, etc.). Where the compounds (I) and (Ia) are of optically-active forms, they can be resolved into d-forms and 1-forms by conventional optical resolution.
Of the starting compounds (II) that are used for producing the compounds (I) and (Ia) or salts thereof of the present invention, compounds (IIa) wherein xe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than  is xe2x80x94COxe2x80x94N less than , D is an ethylene group, and E is  greater than Cxe2x95x90O can be produced, for example, according to the following reaction process (1):
In these formulae, the symbols have the same meanings as above.
The step (1) and the step (2) in the above-mentioned reaction process (1) can be conducted in accordance with known methods for producing the corresponding isoquinolone-skeleton compounds where Ring A and Ring B are both optionally substituted benzene rings (for example, a method described in EP-A-481383, etc.). The step (1) is to produce an amide compound (IV) by reacting the carboxyl group in a compound (III) and the amino group in an iminodiacetonitrile. This reaction may be conducted, in general, in a solvent, by using a compound (III) or a carboxyl-reactive derivative thereof and an iminodiacetonitrile. The reactive derivative includes, for example, acid halides, mixed acid anhydrides, active esters, etc. The solvent includes, for example, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichlroethane, etc., ethers such as ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc., esters such as ethyl acetate, etc., hydrocarbons such as benzene, toluene, etc., pyridine, amides such as N,N-dimethylformamide, etc. The amount of the iminodiacetonitrile is from 1 to 5 molar equivalents or so, preferably from 1 to 3 molar equivalents or so, relative tool of the reactive derivative of the above-mentioned compound (III).
The reaction may be conducted in the presence of a base, by which the reaction is promoted. The base includes, for example, organic bases (e.g., alkylamines such as triethylamine, etc., cyclic amines such as N-methylmorpholine, pyridine, etc., aromatic amines such as N,N-dimethylaniline, N,N-diethylaniline, etc.), and inorganic bases (e.g., alkali metal carbonates such as sodium carbonate, potassium carbonate, etc., alkali metal hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate, etc.). The amount of the base to be used is, for example, from 1 to 5 molar equivalents or so, preferably from 1 to 3 molar equivalents or so, relative to mol of the compound (III) or its reactive derivative. In the reaction of the step (1), employable is a water-immiscible solvent. In this case, water may be added to the reaction system and the reaction is thus conducted in the resulting two-phase system.
The reaction time is generally from 1 to 48-hours or so, preferably from 1 to 24 hours or so. The reaction temperatures falls generally between xe2x88x9210xc2x0 C. and 120xc2x0 C. or so, preferably between about 0xc2x0 C. and 100xc2x0 C. or so.
The step (2) is to obtain a closed compound (V) by subjecting the compound (IV) as formed in the previous step (1) to intramolecular addition-dehydration. In general, a base is employed in this reaction. The base includes, for example, organic bases (e.g., 1,5-diazabicyclo(4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undecen-7-ene (DBU), N-benzyltrimethylammonium hydroxide (Triton B), etc.), and inorganic bases (e.g., alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, etc., alkali metal hydrides such as sodium hydride, potassium hydride, etc., n-butyl lithium, lithium diisopropylamide, etc.). The amount of the base to be used is, for example, from 0.5 to 20 equivalents or so, preferably from 1 to 5 equivalents or so, relative to the compound (IV).
The ring-closure reaction is generally conducted in a solvent. The solvent includes, for example, those as referred to as employable in the step (1). The reaction temperature varies, depending on the type of the base to be used, and falls, for example, between about xe2x88x9280xc2x0 C. and 200xc2x0 C. or so, preferably about xe2x88x9250xc2x0 C. and 150xc2x0 C. or so. The reaction time varies, depending on the starting materials, the base, the reaction temperature and the type of the solvent used, and is, for example, from about 10 minutes to 24 hours or so.
In the previous reaction, an intramolecular adduct is formed as the intermediate. In order to promote the dehydration of the intermediate to obtain a compound (V), it is often preferable to previously add a dehydrating agent (e.g., p-toluenesulfonic acid, methanesulfonic acid, acetic anhydride, etc.) to the reaction system. It is also preferable that the intermediate is isolated and thereafter it is dehydrated in the presence of a dehydrating agent to obtain a compound (V).
The step (3) is to produce a compound (VI) by hydrolyzing the cyano group of the N-cyanomethyl group in the compound (V) as formed in the step (2) into a carboxyl group.
The hydrolysis can be conducted by conventional methods, for example, by treating the compound (V) in a solvent (e.g., alcohols such as methanol, ethanol, propanol, etc., organic acids such as acetic acid, propionic acid, etc., ethers, etc.) in the presence of an acid (preferably, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), at a temperature between about 15xc2x0 C. and 130xc2x0 C. or
The step (4) is to produce a compound (VII) by reducing the carboxyl group in the compound (V) as formed in the step (3) into a hydroxymethyl group. The reduction can be conducted by conventional methods, for example, by converting the carboxyl group in the compound (V) into its reactive derivative (e.g., any of acid halides, mixed acid anhydrides, active esters, esters, etc.), followed by treating the resulting reactive derivative with a reducing agent (e.g., sodium borohydride, aluminium lithium hydride, etc.) in a solvent (e.g., ethers such as tetrahydrofuran, dimethoxyethane, etc.), at a temperature between about 0xc2x0 C. and 100xc2x0 C. or so.
The step (5) is to produce a lactone compound (VIII) by treating the compound (VII) as formed in the previous step (4) under an acidic condition. This step can be conducted under the same conditions as those for the foregoing step (3).
The step (6) is to produce an amide compound (IX) by reacting the compound (VIII) as formed in the previous step (5) with an amine. This reaction can be conducted in the absence or presence of a solvent. The solvent includes, for example, those as referred to hereinabove as employable in the foregoing step (1). The amount of the amine to be used is, for example, from 1 to 50 mols or so, preferably from 1 to 10 mols or so, relative to mol of the compound (VIII). The reaction can be conducted, for example, at a temperature falling between about 15xc2x0 C. and 200xc2x0 C. or so, preferably between about 50xc2x0 C. and 180xc2x0 C. or so. As a result of the step (6), a compound (IX) where X is a hydroxyl group is formed.
The step (7) is to obtain a compound (IIa) by converting the hydroxyl group X in the compound (IX) as formed in the previous step (6) into a removable group The leaving group L includes, for example, a halogen atom (e.g., chlorine, bromine and iodine atoms, etc.), a C1-4 alkanesulfonyloxy group (e.g., methanesulfonyloxy and ethanesulfonyloxy groups, etc.), a C6-10 arylsulfonyloxy group (e.g., benzenesulfonyloxy and p-toluenesulfonyloxy groups, etc.), etc. For the conversion, in general, compounds corresponding to the above-mentioned removable group (e.g., thionyl chloride, thionyl bromide, methanesulfonyl chloride, benzenesulfonyl chloride, etc.) are used. The conversion can be conducted in a solvent (e.g., hydrocarbons such as benzene, toluene, etc., halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, etc., ethers such as tetrahydrofuran, etc., esters such as ethyl acetate, etc.). The reaction temperature falls, for example, between about 0xc2x0 C. and 100xc2x0 C. or so.
Some of the starting compounds (II) can also be produced in accordance with known methods for producing the corresponding compounds where Ring A and Ring B are both homocyclic rings (for example, a method described in EP-585913, etc.) or with reference thereto.
In addition, the compounds of formula (IIa) can also be produced, with reference to the above-mentioned known methods (for example, a method described in EP-481383A1, etc.), via the following compounds (XII) wherein
xe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Yxe2x80x94 is xe2x80x94COxe2x80x94Oxe2x80x94. For example, compounds of the following general formula (IIb) can be produced according to the following reaction process (2).
In these formulae, the symbols have the same meanings as above.
In the reaction process (2), the steps (1) through (4) can be conducted with reference to known methods for producing the corresponding compounds where Ring A and Ring B are both optionally substituted benzene rings (for example, a method described in EP-481383A1, etc.). The steps (5) and (6) are to amidate the carboxyl group in a compound (XII) and a compound (XIII), which can be conducted in the same manner as in the step (1) in the above-mentioned reaction process (1). The step (7) is to convert the pyran ring in the compound (XIV) as formed in the step (5) into a pyridine ring, which can be conducted in the same manner as in the step (4) (see N. A. Santagati, E. Bousquet, G. Romeo, A. Garuso and A. Prato; Bolletino Chimica Farmaceutico, Vol. 125, p. 437, 1986).
Of the starting compounds (II), those of the following formula (IIc):
wherein xe2x80x94Nxe2x95x90C less than  corresponds to xe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than , and the other symbols have the same meanings as above, can be produced by the combination of known methods for producing the corresponding quinoline-skeleton compounds where Ring A and Ring B are both benzene rings (for example, methods described in EP-354994A2, EP-304063A2, etc.) and the methods for producing the above-mentioned compounds (IIa) and (IIb), etc.
Of the compounds (II), those where Ring A and/or Ring B is/are non-aromatic, nitrogen-containing heterocyclic ring(s) can be produced by reducing the corresponding aromatic rings according to the above-mentioned reduction.
The compounds (II) may form salts, which include, for example, salts with inorganic acids (e.g., hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.), salts with organic acids (e.g., acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.), etc. Where the compounds (II) have acidic group(s) such as carboxyl group(s), etc., they may also form salts with inorganic bases (e.g., alkali metals such as sodium, potassium, etc., alkaline earth metals such as calcium, magnesium, etc., ammonia, etc.) or with organic bases (e.g., tri-C1-3 alkylamines such as trimethylamine, triethylamine, etc.).
The compounds represented by the above-mentioned general formula (I), (Ia) also can be produced by, for example, the following reaction process (3).
[wherein all symbols are of the same meaning as defined above, and Lxe2x80x2 stands for a halogen atom (e.g., chlorine, bromine and iodine atoms, etc.), a substituted sulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy and p-toluenesulfonyloxy groups, etc.), etc.].
The above-illustrated. reaction process (3) is alkylation using an alkylating agent in the presence of a base.
The alkylation is conducted, employing approximately 1 to 3 moles each of the base and the alkylating agent relative to one mole of the compound (XV), usually in a solvent for example halogenated hydrocarbons such as dichloromethane, chloroform, etc., nitrites such as acetonitrile, etc., ethers such as dimethoxyethane, tetrahydrofuran, etc., aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc.
Addition of a base to the reaction system advantageously promotes the reaction. As the base, for example, advantageously employed is any of inorganic bases (alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; alkali metal hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; sodium amide; alkoxides such as sodium methoxide, sodium ethoxide, etc.), and organic bases (amines such as trimethylamine, triethylamine, diisopropylethylamine, etc.; cyclic amines such as pyridine, etc.).
As the alkylating agent, use is made of, for example, substituted halides (e.g. chloride, bromide and iodide) and a substituted sulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy, benzensulfonyloxy and p-toluenesulfonyloxy groups, etc.), etc.
While the reaction conditions vary with the combination of the base and the alkylating agent then employed, it is preferable to conduct the reaction usually at 0xc2x0 C. to room temperature for about 1-10 hours.
In the reactions of producing the final compounds and the starting compounds, if the raw materials used have, as substituent(s), amino group(s), carboxyl group(s) and/or hydroxyl group(s), such groups may optionally be protected by ordinary protecting groups such as those generally employed in peptide chemistry, etc. In such cases, if desired, the protecting groups are optionally removed after the reactions to obtain the intended compounds.
The protecting group for amino groups includes, for example, a C1-6 alkylcarbonyl group (e.g., formyl, methylcarbonyl and ethylcarbonyl groups, etc.), a phenylcarbonyl group, a C1-6 alkyl-oxycarbonyl group (e.g., methoxycarbonyl and ethoxycarbonyl groups, etc.), an aryloxycarbonyl group (e.g., phenyloxycarbonyl group, etc.), a C7-10 aralkyl-carbonyl group (e.g., phenyl-C1-4 alkyl-carbonyl such as benzylcarbonyl group, etc.), a trityl group, a phthaloyl group, etc. These protecting groups may optionally be substituted. As substituents for these protecting groups, for example, mentioned are a halogen atom (e.g., fluorine, chlorine, bromine and iodine atoms), a C1-6 alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl and butylcarbonyl groups, etc.), a nitro group, etc. The number of the substituents is from 1 to 3 or so.
The protecting group for carboxyl groups includes, for example, C1-6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl groups, etc.), a phenyl group, a trityl group, a silyl group, etc. These protecting groups may optionally be substituted. As substituents for these protecting groups, for example, mentioned are a halogen atom (e.g., fluorine, chlorine, bromine and iodine atoms), a C1-6 alkylcarbonyl group (e.g., formyl, methylcarbonyl, ethylcarbonyl and butylcarbonyl groups, etc.), a nitro group, etc. The number of the substituents is from 1 to 3 or so.
The protecting group for hydroxyl groups includes, for example, C1-6 alkyl group (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl groups, etc.), a phenyl group, a C7-10 aralkyl group (e.g., benzyl group, etc.), a C1-6 alkylcarbonyl group (e.g., formyl, methylcarbonyl and ethylcarbonyl groups, etc.), an aryloxycarbonyl group (e.g., phenyloxycarbonyl group, etc.), a C7-10 aralkyl-carbonyl group (e.g., benzyloxycarbonyl group, etc.), a pyranyl group, a furanyl group, a silyl group, etc. These protecting groups may optionally be substituted. As substituents for these protecting groups, for example, mentioned are a halogen atom (e.g., fluorine, chlorine, bromine and iodine atoms), a C1-6 alkylcarbonyl group, a phenyl group, a C7-10 aralkyl group, a nitro group, etc. The number of the substituents is from 1 to 4 or so.
To remove the protecting groups, known methods are employable or are referred to. For example, employable are methods of treating. the protected compounds with acids, bases, reducing agents, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like.
The compounds (I) and (Ia) thus produced according to the methods mentioned hereinabove can be isolated and purified by ordinary separation means, for example, by recrystallization, distillation, chromatography, etc. Where the compounds (I) thus produced are of free forms, they can be converted into their salts in accordance with or with reference to known methods (for example, neutralization, etc.). On the contrary, if the compounds (I) are obtained as their salts, they can be converted into the corresponding free forms in accordance with or with reference to known methods.
The compounds (I) and (Ia) or salts thereof of the present invention have tachykinin receptor (especially SP and/or NKA receptor(s)) antagonistic activity in vitro, and have the function of inhibiting the tracheal plasma extravasation induced by capsaicin (in vivo). Capsaicin (a main ingredient of the burning taste of red pepper) is known as a substance that liberates endogenous neuropeptides, such as SP, NKA and calcitonin gene-related peptide(CGRP) by stimulating C-fiber primary sensory nerve that contains such neuropeptides. Thus, the inhibitory action of the plasma extravasation of the compounds (I) and (Ia) or salt thereof of the present invention is considered to be based on the antagonistic activity toward tachykinin receptor.
In addition, the compounds (I) and (Ia) or salts thereof of the present invention are safe as having low toxicity.
Therefore, the compounds (I) and (Ia) or salts thereof of the present invention, thus having such an excellent tachykinin receptor antagonistic effect, are usable as safe medicines for preventing and treating various disorders in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, bovines, sheep, monkeys, man, etc.), such as inflammations or allergic disorders (e.g., atopy, dermatitis, herpes, proriasis, asthma, bronchitis, expectoration, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, conjunctivitis, cystitis, etc.), pain, migraine, neuralgia, pruritus, cough, and additionally disorders of central nervous systems [e.g., schizophrenia, Parkinson""s disease, psychosomatic disorders, dementia (e.g., Alzheimer""s disease, etc.), etc.], digestive diseases (for example, irritable bowel syndrome, ulcerative colitis, Crohn""s disease, diseases caused by a spiral urease-positive gram-negative bacterium such as Helicobacter pylori, etc.), emesis, disorders of micturition (for example, pollakisuria, urinary incontinence etc.), disturbances of circulation (for example, angina pectories, hypertension, cardiac insufficiency, thrombosis, etc.) and immunopathy, etc. More particularly, the compounds (I) and (Ia) or salts thereof of the present invention are usable as a tachykinin receptor antagonist and as an ameliorative preparation for disorders of micturition such as pollakisuria urimary incontinence, etc., and even as medicines for treating such disorders of micturition.
Pharmaceutical preparations comprising compounds (I) and (Ia) or salts thereof of the present invention may be in any solid forms of powders, granules, tablets, capsules, etc., and in any liquid forms of syrups, emulsions, injections, etc.
The preventive and remedial preparations of the present invention can be produced by any conventional methods of, for example, blending, kneading, granulation, tabletting, coating, sterilization, emulsification, etc., in accordance with the forms of the preparations to be produced. For the production of such pharmaceutical preparations, for example, referred to are the particular items in the general remarks for pharmaceutical preparations in the Japanese Pharmacopeia.
In the pharmaceutical preparations of the present invention, the content of the compounds (I) and (Ia) or salts thereof is, though varying depending on the forms of the preparations, generally from 0.01 to 100% by weight or so, preferably from 0.1 to 50% by weight or so, more preferably from 0.5 to 20% by weight or so, relative to the total weight of each preparation.
Where the compounds (I) and (Ia) or salts thereof of the present invention are used in medicines such as those mentioned above, they are, either directly or after having been mixed with suitable, pharmaceutically-acceptable carriers, for example, vehicles (e.g., starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (e.g., starch, arabic gum, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, alginic acid, gelatin, polyvinyl pyrrolidone, etc.), lubricants (e.g., stearic acid, magnesium stearate, calcium stearate, talc, etc.), disintegrators (e.g., calcium carboxymethyl cellulose, talc, etc.), diluents (e.g., water for injection, physiological saline, etc.) and optionally with additives (e.g., stabilizer, preservative, colorant, fragrance, dissolution aid, emulsifier, buffer, isotonic agent, etc.), etc., by ordinary methods, formulated into solid preparations such as powders, fine granules, granules, tablets, capsules, etc., or into liquid preparations such as injections, etc., for peroral or parenteral administration. The dose of the pharmaceutical preparation of the present invention varies, depending on the kind of the compounds (I) and (Ia) or pharmaceutically-acceptable salts thereof, the administration route, the condition and the age of patients, etc. For example, the dose for oral administration of the pharmaceutical preparation to an adult patient suffering from disorders of micturition is, in general, from about 0.005 to 50 mg/kg/day, preferably from about 0.05 to 10 mg/kg/day, more preferably from about 0.2 to 4 mg/kg/day, in terms of the compound (I) or (Ia) or its salt, which may be administered once a day or in two or three portions a day.
The compounds (I) and (Ia) or salts thereof of the present invention may be optionally blended with any desired amounts of any other pharmaceutically-active ingredients to formulate pharmaceutical preparations. Such active ingredients include, for example, drugs for central nervous systems (e.g., imipramine, etc.), anti-cholinergic drugs (e.g., oxybutynin, etc.), xcex11-receptor-blocking drugs (e.g., tamsulosin, etc.), muscle relaxants (e.g., baclofen, etc.), potassium channel-opening drugs (e.g., nicorandil, etc.), potassium channel-blocking drugs (e.g., nifedipine, etc.), etc.
The compounds (I) and (Ia) or salts thereof of the present invention have a high tachykinin receptor antagonistic effect, especially a high substance P receptor antagonistic effect, while having low toxicity, and are safe as medicines. Therefore, the above-mentioned compounds (I) and (Ia) or salts thereof are usable in pharmaceutical compositions, tachykinin receptor antagonists and ameliorative preparations for dysuria.
The present invention will be described in more detail hereinunder, with reference to Examples and Reference Examples. However, the present invention is not restricted by these examples, and changes and modifications can be made within the range which does not deviate the scope of the present invention.
Elution in the column chromatography in the following Reference Examples and Examples was conducted under observation by TLC. (thin layer chromatography), unless otherwise specifically indicated. In the TLC observation, 60F254 produced by Merck Co. was used as the TLC. plate, and the solvent employed in the column chromatography was used as the developing eluent. For the detection, a UV detector was used. As silica gel for the column chromatography, Silica Gel 60 (70-230 mesh) produced by Merck Co. was used. Room temperature as referred to hereinunder generally means temperatures falling between about 10xc2x0 C. and about 35xc2x0 C. For dring the extract solutions, sodium sulfate or magnesium sulfate was used.

Cyclic compounds, their production and use

Abstract: wherein Ring M is a heterocyclic ring having xe2x80x94Nxe2x95x90C less than , xe2x80x94COxe2x80x94N less than  or xe2x80x94CSxe2x80x94N less than  as the partial structure xe2x80x94X{overscore (xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94 xe2x80x94)} Y less than ; Ra and Rb are bonded to each other to form Ring A, or they are the same or different and represent, independently, a hydrogen atom or a substituent on the Ring M; Ring A and Ring B represent, independently, an optionally substituted homocyclic or heterocyclic ring, and at least one of them is optionally substituted heterocyclic ring; Rng C is optionally substituted homocyclic or heterocyclic ring; Rng Z is an optionally substituted ring; and n represents an integer of from 1 to 6, or a salt thereof, which has an excellent tachykinin receptor antagonistic effect, and their production, and pharmaceutical compositions.