Takeda Chemical Industries, Inc.

Shinji Terao

Kohei Nishikawa

Yoshitaka Maki

Mitsuru Shiraishi

Isuke Imada

Hisayoshi Okazaki

Minoru Hirata

Kaneyoshi Kato

Isao Minamida

Mitsuo Numata

Masayoshi Yamaoka

Toshio Miyawaki

Setsuo Harada

Mitsuru Kawada

Masazumi Watanabe

Katsumi Itoh

Michael John Tisdale

Akinobu Nagaoka

Noriko Watanabe

Yoshio Imashiro

Mitsuyoshi Azuma

Use of quinone and hydroquinone derivatives for the treatment of cachexia

Quinone derivatives of the general formula: ##STR1## (wherein R.sup.1 and R.sup.2 are the same or different, and independently are a hydrogen atom or a methyl or methoxy group, or R.sup.1 and R.sup.2 combine with each other to represent --CH.dbd.CH--CH.dbd.CH--; R.sup.3 is a hydrogen atom or a methyl group; R.sup.4 is an aliphatic, aromatic or heterocyclic group which may be substituted; R.sup.5 is a methyl or methoxy group, a hydroxymethyl group which may be substituted or a carboxyl group which may be esterified or amidated; Z is a group represented by --C.tbd.C--, --CH.dbd.CH--, ##STR2## n is an integer of 0 to 10; m is an integer of 0 to 3; k is an integer of 0 to 5, provided, however, that in the case of m being 2 or 3, Z and k can vary arbitrarily within the bracketed repeating units) are novel compounds, possess metabolism ameliorating action for polyunsaturate fatty acids, particularly production inhibitory activity of lipid peroxides (antioxidant activity), thromboxane A.sub.2 receptor antagonism, or production inhibitory activity of 5-lipoxygenase metabolites in mammals, and of use as drugs, such as antiasthmatic, antiallergic agent and cerebral-circulatory metabolism ameliorating agent.

Quinone derivatives, their production and use

Quinone derivatives represented by the general formula ##STR1## (wherein, R.sup.1 and R.sup.2, the same or different, refer to hydrogen atom, methyl or methoxymethyl group, or R.sup.1 and R.sup.2 bind together to form --CH.dbd.CH--CH.dbd.CH--; R.sup.3 is hydrogen atom or methyl group; R.sup.4 is nitrogen-containing heterocyclic group which may be substituted; R.sup.5 is hydrogen atom, methyl group, hydroxymethyl group which may be substituted, or carboxyl group which may be esterified or amidated; Z is ##STR2## (wherein, R' is hydrogen atom or methyl group); n is an integer from 0 through 12, m is an integer from 0 through 3, and k is an integer from 0 through 7, providing that, when m is 2 or 3, Z and k are able to vary appropriately in the repeating unit shown in []), and the hydroquinone derivatives thereof, are novel compounds, possess improvement effects of metabolism of poly unsaturated fatty acids, particularly two or more of inhibition of production of fatty acid peroxides, inhibition of production of metabolites in 5-lipoxygenase pathway, inhibition of thromboxane A.sub.2 synthetase, thromboxane A.sub.2 receptor antagonism and scavenging action of active oxygen species, and of use as drugs, such as antithrombotics, anti-vascular constriction agents, anti-asthma agent, antiallergic agents, therpeutics for psoriasis, agents for improvement in heart, brain and cardiovascular systems, therapeutics for nephritis, active oxygen-eliminating agents, anticancer agents, agents for improvement of control of arachidonate cascade products, etc.

Quinone derivatives of the general formula: ##STR1## (wherein R.sup.1 and R.sup.2 are the same or different, and independently are a hydrogen atom or a methyl or methoxy group, or R.sup.1 and R.sup.2 combine with each other to represent --CH.dbd.CH--CH.dbd.CH--R.sup.3 is a hydrogen atom or a methyl group; R.sup.4 is an aliphatic, aromatic or heterocyclic group which may be substituted; R.sup.5 is a methyl or methoxy group, a hydroxymethyl group which may be substituted or a carboxyl group which may be esterified or amidated; Z is a group represented by --C.dbd.C--, --CH.dbd.CH--, ##STR2## n is an integer of 0 to 10; m is an integer of 0 to 3; k is an integer of 0 to 5, provided, however, that in the case of m being 2 or 3, Z and k can vary arbitrarily within the bracketed repeating units) are novel compounds, possess metabolism ameliorating action for polyunsaturated fatty acids, particularly production inhibitory activity of lipid peroxides (antioxidant activity), thromboxane A.sub.2 receptor antagonism, or production inhibitory activity of 5-lipoxygenase metabolites in mammals, and of use as drugs, such as antiasthmatic, antiallergic agent and cerebral-circulatory metabolism ameliorating agent.

Quinone derivatives represented by the general formula ##STR1## (wherein, R.sup.1 and R.sup.2, the same or different, refer to hydrogen atom, methyl or methoxymethyl group, or R.sup.1 l R.sup.2 bind together to form --CH.dbd.CH--CH.dbd.CH--; R.sup.3 is hydrogen atom or methyl group; R.sup.4 is nitrogen-containing heterocyclic group which may be substituted; R.sup.5 is hydrogen atom, methyl group, hydroxymethyl group which may be substituted, or carboxyl group which may be esterified or amidated; Z is ##STR2## (wherein, R' is hydrogen atom or methyl group); n is an integer from 0 through 12, m is an integer from 0 through 3, and k is an integer from 0 through 7, providing that, when m is 2 or 3, Z and k are able to vary appropriately in the repeating unit shown in []), and the hydroquinone derivatives thereof, are novel compounds, possess improvement effects of metabolism of poly unsaturated fatty acids, particularly two or more of inhibition of production of fatty acid peroxides, inhibition of production of metabolites in 5-lipoxygenase pathway, inhibition of thromboxane A.sub.2 synthetase, thromboxane A.sub.2 receptor antagonism and scavenging action of active oxygen species, and of use as drugs, such as antithrombotics, anti-vascular constriciton agents, anti-asthma agent, antiallergic agents, therpeutics for psoriasis, agents for improvement in heart, brain and cardiovascular systems, therapeutics for nephritis, active oxygen-eliminating agents, anticancer agents, agents for improvement of control of arachidonate cascade products, etc.

A compound having the formula (I) or (II) ##STR1## wherein R.sup.1 is a hydrogen atom or an organic residue bonded via a carbon atom, R.sup.2 is a hydrogen atom or a N-protecting group, --COR.sup.3 is an optionally esterified or amidated carboxyl group, R.sup.4 and R.sup.5 are the same or different and respectively a hydrogen atom or an acyl group or a chain or alicyclic hydrocarbon group optionally having an aryl substituent, R.sup.6 is NOH or O, n is an integer of 0 to 3, or R.sup.4 and R.sup.5 together with the adjacent nitrogen atom may form a ring or an optionally substituted benzylidene amino group, which is useful therapeutics of brain dysfunction.

Cerebral function ameliorating agents related to Tan-950 A

Quinone derivatives represented by the general formula ##STR1## (wherein, R.sup.1 and R.sup.2, the same or different, refer to hydrogen atom, methyl or methoxymethyl group, or R.sup.1 and R.sup.2 bind together to form --CH.dbd.CH--CH.dbd.CH--; R.sup.3 is hydrogen atom or methyl group; R.sup.4 is nitrogen-containing heterocyclic group which may be substituted; R.sup.5 is hydrogen atom, methyl group, hydroxymethyl group which may be substituted, or carboxyl group which may be esterified or amidated; Z is ##STR2## --CH.dbd.CH--, ##STR3## or ##STR4## (wherein, R' is hydrogen atom or methyl group); n is an integer from 0 through 12, m is an integer from 0 through 3, and k is an integer from 0 through 7, providing that, when m is 2 or 3, Z and k are able to vary appropriately in the repeating unit shown in [ ]), and the hydroquinone derivatives thereof, are novel compounds, possess improvement effects of metabolism of poly unsaturated fatty acids, particularly two or more inhibitition of production of fatty acid peroxides, inhibition of production of metabolites in 5-lipoxygenase pathway, inhibition of thromboxane A.sub.2 synthetase, thromboxane A.sub.2 receptor antagonism and scavenging action of active oxygen species, and of use as drugs, such as antithrombotics, anti-vascular constriction agents, anti-asthma agent, antiallergic agents, therpeutics for psoriasis, agents for improvement in heart, brain and cardiovascular systems, therapeutics for nephritis, active oxygen-eliminating agents, anticancer agents, agents for improvement of control of arachidonate cascade products, etc.

Certain benzoquinones, naphthoquinones and derivatives thereof which

An ascorbic acid derivative of the formula: ##STR1## wherein R.sup.1 is organic residue having molecular weight of from 15 to 700, R.sup.2 is hydrogen or hydroxyl, R.sup.3 is hydrogen, acyl, optionally substituted phosphono or sulfo, and R.sup.3 and hydroxyl or R.sup.2 may form acetal residue or ketal residue, and a salt thereof are provided. The compound [I] and salts thereof have antioxidant activity and excellent prophylactic and improving actions on disorders of circulatory functions, and they are usefule as antioxidant agent for food and as agents of prophylaxis and improvement of circulatory functional disorders.

Pharmaceutical compositions containing certain ascorbic acid derivatives

A novel benzoquinone derivative of the general formula: ##STR1## [wherein R.sub.1 and R.sub.2 are the same or different and each is methyl or methoxy; n is an integer of 0 to 21; m is 0 or 1, Z is a group of the formula: ##STR2## (wherein R.sub.3 and R.sub.4 are the same or different and each is hydrogen or an alkyl group which may optionally be substituted or, R.sub.3 and R.sub.4 together with the adjacent nitrogen atom form a morpholino group), a group of the formula: --COR.sub.5 (wherein R.sub.5 is an .alpha.-amino acid residue or a substituted or unsubstituted glucosamine residue), a group of the formula: ##STR3## (wherein R.sub.6 is a divalent hydrocarbon group of 1 to 3 carbon atoms), a group of the formula: ##STR4## (wherein R.sub.6 has the same meaning as defined above) or a group of the formula: ##STR5## (wherein l is an integer of 1 to 4 and R.sub.7 is hydroxy, methoxy or methyl)] has protocollagen-proline hydroxylase inhibiting activity, collagen biosynthesis inhibiting activity and 5-lipoxygenase suppressant activity, and is useful for the prevention and treatment of such diseases as pulmonary fibrosis, hepatocirrhosis, nephrosclerosis, arteriosclerosis, scleroderma, myelofibrosis and chronic arthritis or for the prevention and treatment of asthma, allergic rhinitis, urticaria, etc.

Benzoquinone derivatives and production thereof

The present invention relates to a compound of the formula: ##STR1## wherein Y is a chemical bond, oxygen atom, phenyleneoxy, or oxyphenyleneoxy; R.sup.1 is hydrogen or hydrocarbon residue; and R.sup.2 is hydrocarbon residue having two or more carbon atoms, production and use thereof. The compound (I) of the present invention has an antioxidation activity and activities of preventing or improving functional disorders due to biologically active oxygen species, thus being useful as a pharmaceutical agent for prophylaxis and therapy of disorders in the circulatory system.

Hydroxybutenolide derivatives, production and use thereof

The present invention relates to a compound of the formula: ##STR1## wherein X is sulfur or optionally substituted imino group; Y is a bond, oxygen, phenylene, phenyleneoxy, or oxyphenyleneoxy; R.sup.1 is hydrogen or optionally substituted hydrocarbon residue; R.sup.2 is optionally substituted hydrocarbon residue; and R.sup.1 may form, together with the imino-nitrogen atom as X, a nitrogen-containing 5- to 7-membered ring, production and use thereof. The compound (I) of the present invention has an anti-oxidation activity and activities of preventing or improving functional disorders due to biologically active oxygen species, thus being useful as a pharmaceutical agent for prophylaxis and therapy of disorders in the circulatory system.

4-Hydroxy-3-pyrrolin-2-ones and treatment of circulatory disorders

A novel benzoquinone derivative of the general formula: ##STR1## [wherein R.sub.1 and R.sub.2 are the same or different and each is methyl or methoxy; n is an integer of 0 to 21; m is 0 or 1, Z is a group of the formula: ##STR2## (wherein R.sub.3 and R.sub.4 are the same or different and each is hydrogen or an alkyl group which may optionally be substituted or, R.sub.3 and R.sub.4 together with the adjacent nitrogen atom form a morpholino group), a group of the formula: --COR.sub.5 (wherein R.sub.5 is an .alpha.-amino acid residue or a substituted or unsubstituted glucosamine residue), a group of the formula: ##STR3## (wherein R.sub.6 is a divalent hydrocarbon group of 1 to 3 carbon atoms), a group of the formula: ##STR4## (wherein R.sub.6 has the same meaning as defined above) or a group of the formula: --CH.dbd.CH).sub.l COR.sub.7 (wherein l is an integer of 1 to 4 and R.sub.7 is hydroxy, methoxy or methyl)] has protocollagen-proline hydroxylase inhibiting activity, collagen biosynthesis inhibiting activity and 5-lipoxygenase suppressant activity, and is useful for the prevention and treatment of such diseases as pulmonary fibrosis, hepatocirrhosis, nephrosclerosis, arteriosclerosis, scleroderma, myelofibrosis and chronic arthritis or for the prevention and treatment of asthma, allergic rhinitis, urticaria, etc.

A compound of the formula ##STR1## wherein R is a lower alkyl group, R.sup.0 is hydrogen or an acyl group, R.sup.1 and R.sup.2 are lower alkyl groups which may optionally be substituted or wherein R.sup.1 and R.sup.2 are combined to form a butadienylene group which may optionally be substituted, R.sup.3 and R.sup.4 are hydrogen or alkyl groups which may optionally be substituted or wherein R.sup.3 and R.sup.4 are combined to form a polymethylene group, and R.sup.5 is a lower alkyl, aromatic or heterocyclic group which may optionally be substituted or a pharmaceutically acceptable salt thereof, exerts cardiovascular system improving action and antiallergic action and can be used as pharmaceutics, e.g. antithromotics, antiallergic agents etc.

Coumaran derivatives and their pharmaceutical use

Quinone derivatives represented by the general formula ##STR1## (wherein, R.sup.1 and R.sup.2, the same or different, refer to a hydrogen atom, methyl or methoxymethyl group, or R.sup.1 and R.sup.2 bind together to form --CH.dbd.CH--CH.dbd.CH--; R.sup.3 is a hydrogen atom or methyl group; R.sup.4 is a nitrogen-containing heterocyclic group which may be substituted; R.sup.5 is a hydrogen atom, methyl group, hydroxymethyl group which may be substituted, or a carboxyl group which may be esterified or amidated; Z is ##STR2## (wherein, R' is hydrogen atom or methyl group); n is an integer from 0 through 12, m is an integer from 0 through 3, and k is an integer from 0 through 7, providing that, when m is 2 or 3, Z and k are able to vary appropriately in the repeating unit shown in [ ]), and the hydroquinone derivatives thereof, are novel compounds, possess improvement effects of metabolism of polyunsaturated fatty acids, particularly two or more of inhibition of production of fatty acid peroxides, inhibition of production of metabolites in 5-lipoxygenase pathway, inhibition of thromboxane A.sub.2 synthetase, thromboxane A.sub.2 receptor antagonism and scavenging action of active oxygen species, and of use as drugs, such as antithrombotics, anti-vascular constriction agents, anti-asthma agent, antiallergic agents, therapeutics for psoriasis, agents for improvement in heart, brain and cardiovascular systems, therapeutics for nephritis, active oxygen-eliminating agents, anticancer agents, agents for improvement of control of arachidonate cascade products, etc.

Certain benzoquinones, naphthoquinones, corresponding hydroquinones

The present invention relates to a treatment of cataract by administering a compound of the formula: ##STR1## wherein n is an integer of 8 to 20, and use thereof. The compound (I) of this invention has an excellent therapeutic effect against various types of cataract.

Growing community of inventors

Toyonaka, Japan

Shinji Terao