Chugai Seiyaku Kabushiki Kaisha

Denki Kagaku Kogyo Kabushiki Kaisha

Takenori Ishizawa

Haruhiko Sato

Hiroshi Koga

Yukio Suzuki

Hiroharu Matsuoka

Tadakatsu Takahashi

Hiroyuki Nabata

Nobuaki Kato

Noriaki Maruyama

Koichi Takahashi

Tadashi Morikawa

Hitoshi Ikeya

Tatsuya Tamura

Akira Okamachi

Yoshinobu Higuchi

Masashi Watanabe

Noriyuki Izutani

Akie Honma

Vladimir A Khlebnikov

Tatsuya Kato

It was discovered that a cyclic sulfamidate can be produced by reacting an amino acid derivative with a cyclization reagent. In addition, it was discovered that an O-substituted serine derivative can be produced by reacting a cyclic sulfamidate with an alcohol.

O-substituted serine derivative production method

An object of the present invention is to provide a hyaluronic acid-methotrexate conjugate useful as a therapeutic drug for joint diseases. There is provided a hyaluronic acid-methotrexate conjugate useful as a therapeutic drug for joint diseases, wherein methotrexate is conjugated with a carboxyl group of hyaluronic acid through a linker containing a peptide chain consisting of 1 to 8 amino acids.

Hyaluronic acid-methotrexate conjugate

An object of the present invention is to provide a hyaluronic acid-methotrexate conjugate useful as a therapeutic drug for joint disorders. There is provided a hyaluronic acid-methotrexate conjugate useful for the treatment of joint disorders, wherein methotrexate is conjugated with a hydroxy group of hyaluronic acid through a linker containing a peptide chain consisting of 1 to 8 amino acids, and the linker is conjugated with the hyaluronic acid through a carbamate group.

There is provided a compound represented by the general formula (1): wherein Het represents an optional substituted heterocylic group Aand Aeach independently represent &#x2014;CH&#x2550;, etc.; Arepresents &#x2014;CH&#x2014;, etc.; Rrepresents a 4-fluorophenyl group, etc.; Rrepresents an alkyl group; n represents 0, 1 or 2, provided that when Aand Aboth are &#x2014;CH&#x2550;, Arepresents &#x2014;CH&#x2014; or &#x2014;SO&#x2014;, which is an indole derivative or a mono- or diazaindole derivative that has COX-2 inhibitory activity and is useful as a pharmaceutical, such as an anti-inflammatory agent, or addition salts thereof with a pharmaceutically acceptable acid or base, or hydrates thereof.

Indole derivative having heterocycle and mono- or diazaindole derivative

There is provided a compound represented by the general formula (1):wherein Het represents an optional substituted heterocylic group Aand Aeach independently represent &#x2014;CH&#x2550;, etc.; Arepresents &#x2014;CH&#x2014;, etc.; Rrepresents a 4-fluorophenyl group, etc.; Rrepresents an alkyl group; n represents 0, 1 or 2, provided that when Aand Aboth are &#x2014;CH&#x2550;, Arepresents &#x2014;CH&#x2014; or &#x2014;SO&#x2014;, which is an indole derivative or a mono- or diazaindole derivative that has COX-2 inhibitory activity and is useful as a pharmaceutical, such as an anti-inflammatory agent, or addition salts thereof with a pharmaceutically acceptable acid or base, or hydrates thereof.

Heterocyclic indole derivatives and mono- or diazaindole derivatives

Starting, for example, from 1-fluoro-2-fluoromethyl-3-butyn-2-yl 4-trifluoromethylphenyl; ether, N-(2-cyanoethyl)-5-fluoro-4-fluoromethyl-4-(4-trifluoromethylphenoxy)-2-pentynamide is produced and then cyclized to synthesize 2,2-bis(fluoromethyl)-N-(2-cyanoethyl)-6-trifluoromethyl-2H-1-benzopyran-4-carboxamide. The invention processes for producing 4-substituted benzopyran derivatives involve fewer steps, feature greater safety and allow for easier purification than the prior art processes.

Processes for the preparation of 4-substituted benzopyran derivatives

Novel benzopyran and benzoxazine derivatives represented by the general formula: wherein R.sub.1 and R.sub.2 represent a lower haloalkyl group, R.sub.3 represents a hydrogen atom, etc., R.sub.4 represents a heterocyclic group or A--O-- wherein A represents a cyclic structure, etc., R.sub.5 and R.sub.6 represent a lower haloalkyl, X represents .dbd.N--, N.fwdarw.O, etc, are disclosed. These compounds exhibit K.sup.+ channel opening activating and can be widely used as an anti-asthma drug, an anti-epilepsy drug, etc.

Benzopyran and benzoxazine derivatives

Novel benzopyran and benzoxazine derivatives represented by the general formula: ##STR1## wherein R.sub.1 and R.sub.2 represent a lower haloalkyl group, R.sub.3 represents a hydrogen atom, etc., R.sub.4 represents a heterocyclic group or A--O-- wherein A represents a cyclic structure, etc., R.sub.5 and R.sub.6 represent a lower haloalkyl, X represents .dbd.N--, N.fwdarw.O, etc, are disclosed. These compounds exhibit K.sup.+ channel opening activating and can be widely used as an anti-asthma drug, an anti-epilepsy drug, etc.

Growing community of inventors

Gotenba, Japan

Takenori Ishizawa