Mitsubishi Tanabe Pharma Corporation

Shanghai Pharmaceuticals Holding Co., Ltd.

Toru Iijima

Takayuki Kawaguchi

Hidenori Akatsuka

Guangxin Xia

Jun Murakami

Jingkang Shen

Hiroshi Sugama

Jianshu Xie

Tatsuya Watanabe

Yoichi Takahashi

Miki Hirai

Takashi Mitsui

Yasuo Yamamoto

Masamichi Morimoto

Nobumasa Awai

Takeshi Hamada

Yoshihiro Sugiura

Atsushi Moroda

Kenichi Toyama

Yukie Okamoto

Kaori Tomikawa

Tomoyuki Okabe

Naoko Ueda

Yasunori Tsuboi

Huixin Wan

Jiansheng Han

Guohui Jia

Yuko Togashi

The present invention provides novel pharmaceutically acceptable salts of a morpholine derivative, including a malate, a tartrate, a hydrochloride, an acetate, and a naphthalene disulfonate thereof, wherein the tartrate has 3 crystal salt forms: crystal form A, crystal form B and dihydrate; the malate, the hydrochloride, and the acetate each have one crystal salt form; the naphthalene disulfonate is amorphous. When compared to the known morpholine derivative free base, the present invention has one or more improved properties, e.g., a better crystalline state, greatly improved water solubility, light stability and thermal stability, etc. The present invention further provides preparation methods for the salts of morpholine derivative and the crystal forms thereof, pharmaceutical compositions and use thereof.

Salts of morpholine derivative, crystal forms thereof, processes for producing the same, pharmaceutical compositions including the same, and use thereof

The present invention provides a nitrogen-containing saturated heterocyclic compound of the formula [I]: wherein Ris a cycloalkyl group and the like, Ris an optionally substituted aryl and the like, R is a lower alkyl and the like, T is a carbonyl group, Z is &#x2014;O&#x2014; and the like, and Rto Rare the same or different and a hydrogen atom and the like; or a pharmaceutically acceptable salt, that is useful as a renin inhibitor.

Nitrogen-containing saturated heterocyclic compound

The present invention provides an industrially advantageous method for producing a 1,4-benzoxazine compound useful as a medicine while avoiding safety and health risks. Specifically, the present invention provides a method for producing a 1,4-benzoxazine compound [A], which comprises the three steps in the following scheme, namely, a step of converting the amino group at 7-position in a compound [a] into a dimesylamino group, a step of coupling a compound [b] with a boronic acid compound, and a step of converting the 7-position in a compound [c] into a monomesylamino group.  In the above scheme, Ms is a methanesulfonyl group, and each of R' and R&#x2033; is a hydrogen atom etc.

Method for producing 1,4-benzoxazine compound

The present invention provides a nitrogen-containing saturated heterocyclic compound of the formula [I] which is useful as a renin inhibitor. wherein Ris a cycloalkyl group or an alkyl,

Renin inhibitor

The present invention provides a nitrogen-containing saturated heterocyclic compound of the formula [I]: wherein Ris a cycloalkyl group and the like, Ris an optionally substituted aryl and the like, R is a lower alkyl and the like, T is a carbonyl group, Z is &#x2014;O&#x2014; and the like, and Rto Rare the same or different and a hydrogen atom and the like;or a pharmaceutically acceptable salt, that is useful as a renin inhibitor.

The present invention provides a morpholine derivative of the formula [I]; wherein Ris a substituted alkyl group, an optionally substituted aryl group, an optionally substituted heterocyclo group, a cycloalkyl group or an alkyl group; Ris a substituted alkyl group, an optionally substituted aryl group, an optionally substituted heterocyclo group, an optionally substituted alkylcarbonyl group, an optionally substituted arylcarbonyl group, an optionally substituted heterocyclo-substituted carbonyl group or a cycloalkylcarbonyl group; T is a methylene group or a carbonyl group; R, R, Rand Rare the same or different and a hydrogen atom, an optionally substituted carbamoyl group or an optionally substituted alkyl group;or pharmaceutically acceptable salts thereof. These compounds are useful as a renin inhibitor.

Morpholine derivative

The present invention provides a novel fused bicyclic compound having an affinity to a receptor of mineral corticoid (MR), shown by the formula [I]: wherein the ring A is a benzene ring having a substituent R, fused to an adjacent 6-membered heterocyclic ring and further optionally having a substituent(s) other than R, Ris an alkylsulfonylamino group etc.,

Fused bicyclic compound

The present invention relates to a compound, useful as a mineralocorticoid receptor-modulating agent, of the following formula [I]: wherein Ring A is a benzene ring optionally having a substituent(s) other than Retc, Ris a group of the formula: RSONH&#x2014; etc, Ris an alkyl group etc, Rand Rare each a hydrogen atom, a phenyl group, an optionally substituted alkyl group etc, X is an oxygen atom etc, Y is a group of the formula: &#x2014;C(&#x2550;O)&#x2014; etc, Ar is an optionally substituted aryl group or an optionally substituted heteroaryl group, Q is a single bond, an alkylene group etc, or a pharmaceutically acceptable salt thereof.

Benzoxazines and related nitrogen-containing heterobicyclic compounds useful as mineralocorticoid receptor modulating agents

The present invention provides a condensed furan compound of the formula (I): wherein Ring X is benzene, pyridine, or the like; Y is an optionally substituted amino, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted saturated heterocyclic group, an optionally substituted unsaturated heterocyclic group; A is a single bond, lower alkylene, lower alkenylidene, lower alkenylene or an oxygen atom; Ris hydrogen or the like; and, Ris hydrogen, or the like, or pharmaceutically acceptable salts thereof, which is useful as a medicament, particularly, as an activated blood coagulation factor X inhibitor.

Condensed furan compounds

The present invention provides a carbamoyl-type benzofuran derivative of the formula [1]: wherein Ring Z is a group of the formula: etc.; A is a single bond, and the like; Y is a cycloalkanediyl group, etc.; Rand Rare the same or different and each is an optionally substituted lower alkyl group, etc.; Ris a halogen atom, etc.; Ring B of the formula: is an optionally substituted benzene ring; and Ris a hydrogen atom. etc., or a pharmaceutically acceptable salt thereof, which is useful as an FXa inhibitor.

Carbamoyl-type benzofuran derivatives

The present invention provides a benzofuran derivative of the formula [1]: wherein x is a group of the formula: &#x2014;N&#x2550; or &#x2014;CH&#x2550;; Y is an optionally substituted amino group, an optionally substituted cycloalkyl group or an optionally substituted saturated heterocyclic group; A is a single bond, a carbon chain optionally having a double bond within or at the end(s) of the chain, or an oxygen atom; Ris a hydrogen atom or a halogen atom; Ring B is an optionally substituted benzene ring; and Ris a hydrogen atom, or a pharmaceutically acceptable salt thereof, which is useful as a medicament, especially as an activated blood coagulation factor X inhibitor.

Benzofuran derivative

Fused furan compound

The present invention provides an amide-type carboxamide derivative of the formula [1]: wherein X is a group of the formula: &#x2014;N&#x2550; or the formula: &#x2014;CH&#x2550;; Ris a halogen atom, a lower alkyl group, and the like; Ris a group of the formula: and the like; Yand Yare the same or different and each is a group selected from a halogen atom, a lower alkyl group, a lower alkoxy group, and the like; Ring A is phenyl group, and the like, or a pharmaceutically acceptable salt thereof, which is useful as an inhibitor of FXa.

Growing community of inventors

Osaka, Japan

Toru Iijima