Claims for Patent: 7,285,572

Summary for Patent: 7,285,572

Title:	CaSR antagonist
Abstract:	The present invention provides a compound having a calcium-sensitive receptor antagonistic action, a pharmaceutical composition containing the compound, particularly a calcium receptor antagonist and a therapeutic drug for osteoporosis. A compound represented by the following formula (1), a pharmaceutically acceptable salt thereof or an optically active form thereof: ##STR00001## wherein each symbol is as defined in the description.
Inventor(s):	Shinagawa; Yuko (Osaka, JP), Inoue; Teruhiko (Osaka, JP), Kiguchi; Toshihiro (Osaka, JP), Ikenogami; Taku (Osaka, JP), Ogawa; Naoki (Osaka, JP), Nakagawa; Takashi (Osaka, JP), Shindo; Masanori (Osaka, JP), Soejima; Yuki (Osaka, JP)
Assignee:	Japan Tobacco Inc. (Tokyo, JP)
Application Number:	11/286,378
Patent Claims:	1. A compound represented by the following formula (1), an optically active form thereof, or a pharmaceutically acceptable salt thereof: ##STR00119## ring A is a C.sub.3-6 cycloalkyl group, ##STR00120## wherein R.sup.1 is a C.sub.1-6 alkyl group or R.sup.AO--C(.dbd.O)--X--(O)n-, wherein R.sup.A is a hydrogen atom, a C.sub.1-6 alkyl group or R.sup.BO--C(.dbd.O)O--C.sub.1-6 alkylene- (wherein R.sup.B is a C.sub.1-6 alkyl group or a C.sub.3-6 cycloalkyl group), X is a C.sub.1-6 alkylene group, a C.sub.2-4 alkenylene group, a C.sub.2-4 alkynylene group, ##STR00121## (wherein m is an integer of 0 to 6) or ##STR00122## and n is 0 or 1, R.sup.2 is a carboxy-C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy-carbonyl-C.sub.1-6 alkyl group, a carbamoyl-C.sub.1-6 alkyl group, a C.sub.1-7 acylamino-C.sub.1-6 alkyl group, a hydroxycarbamoyl group, a C.sub.1-6 alkylsulfonyl-carbamoyl group, an oxalo group, a phosphoric acid group optionally esterified by a C.sub.1-6 alkyl group, R.sup.AO--C(.dbd.O)-- (R.sup.A is as defined above) or a 5- or 6-membered heterocyclic residue having 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (said heterocyclic residue is optionally substituted by an oxo group), R.sup.3 and R.sup.4 are the same or different and each is a hydrogen atom, a cyano group, a halogen atom, a C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a halo C.sub.1-6 alkyl group or a halo C.sub.1-6 alkoxy group, R.sup.5 is a C.sub.1-6 alkyl group or a C.sub.3-6 cycloalkyl group, R.sup.6 is a hydrogen atom or R.sup.C (wherein R.sup.C is a C.sub.1-7 acyl group optionally substituted by a carboxyl group), R.sup.7, R.sup.8 and R.sup.9 are the same or different and each is a hydrogen atom, a C.sub.1-6 alkyl group, a C.sub.2-4 alkenyl group, a halogen atom, a halo C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a halo C.sub.1-6 alkoxy group, or a carboxyl group, or the adjacent R.sup.7 and R.sup.8 are joined to form --CH.dbd.CH--CH.dbd.CH--, provided that (1) when ring A is a group of the formula (a) and R.sup.1 is a C.sub.1-6 alkyl group, then R.sup.6 is R.sup.C, (2) when ring A is a group of the formula (b) and R.sup.2 is a carboxyl group or a C.sub.1-6 alkoxy-carbonyl group, then R.sup.7 is a C.sub.2-4 alkenyl group, (3) when ring A is a group of the formula (b) and R.sup.2 is a hydroxycarbamoyl group, then R.sup.3 is a hydrogen atom, or (4) when ring A is a group of the formula (a), R.sup.1 is R.sup.AO--C(.dbd.O)--X--(O)n- and X is ##STR00123## then n is 0. 2. The compound of claim 1, wherein ring A is ##STR00124## R.sup.1 is a C.sub.1-6 alkyl group or R.sup.AO--C(.dbd.O)--X--(O)n-, wherein R.sup.A is a hydrogen atom, X is a C.sub.1-6 alkylene group, a C.sub.2-4 alkenylene group, a C.sub.2-4 alkynylene group, ##STR00125## (wherein m is an integer of 0 to 6) or ##STR00126## and n is 0, R.sup.5 is a C.sub.1-6 alkyl group or a C.sub.3-6 cycloalkyl group, R.sup.6 is a hydrogen atom, R.sup.7, R.sup.8 and R.sup.9 are the same or different and each is a hydrogen atom, a C.sub.1-6 alkyl group, a C.sub.2-4 alkenyl group, a halogen atom, a halo C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a halo C.sub.1-6 alkoxy group, or a carboxyl group, or the adjacent R.sup.7 and R.sup.8 are joined to form --CH.dbd.CH--CH.dbd.CH--, an optically active form thereof, or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1, wherein ring A is ##STR00127## R.sup.2 is a carboxy-C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy-carbonyl-C.sub.1-6 alkyl group, a carbamoyl-C.sub.1-6 alkyl group, a C.sub.1-7 acylamino-C.sub.1-6 alkyl group, or a hydroxycarbamoyl group, R.sup.3 and R.sup.4 are the same or different and each is a hydrogen atom, a cyano group, a halogen atom, a C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a halo C.sub.1-6 alkyl group or a halo C.sub.1-6 alkoxy group, R.sup.5 is a C.sub.1-6 alkyl group or a C.sub.3-6 cycloalkyl group, R.sup.6 is a hydrogen atom, R.sup.7, R.sup.8 and R.sup.9 are the same or different and each is a hydrogen atom, a C.sub.1-6 alkyl group, a C.sub.2-4 alkenyl group, a halogen atom, a halo C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a halo C.sub.1-6 alkoxy group, or a carboxyl group, or the adjacent R.sup.7 and R.sup.8 are joined to form --CH.dbd.CH--CH.dbd.CH--, an optically active form thereof, or a pharmaceutically acceptable salt thereof. 4. The compound of claim 1, which is selected from the group consisting of the following structural formulas, an optically active form thereof, or a pharmaceutically acceptable salt thereof: ##STR00128## ##STR00129## ##STR00130## ##STR00131## ##STR00132## ##STR00133## 5. A compound represented by the following formula (1'), a pharmaceutically acceptable salt thereof or an optically active form thereof: ##STR00134## ring A is a C.sub.3-6 cycloalkyl group, ##STR00135## R.sup.1 is a C.sub.1-6 alkyl group or R.sup.AO--C(.dbd.O)--X--(O)n-, wherein R.sup.A is a hydrogen atom, a C.sub.1-6 alkyl group or R.sup.BO--C(.dbd.O)O--C.sub.1-6 alkylene- (wherein R.sup.B is a C.sub.1-6 alkyl group or a C.sub.3-6 cycloalkyl group), X is a C.sub.1-6 alkylene group, a C.sub.2-4 alkenylene group, a C.sub.2-4 alkynylene group, or ##STR00136## (wherein m is an integer of 0 to 6), and n is 0 or 1, R.sup.2 is a carboxy-C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy-carbonyl-C.sub.1-6 alkyl group, a carbamoyl-C.sub.1-6 alkyl group, a C.sub.1-7 acylamino-C.sub.1-6 alkyl group, a hydroxycarbamoyl group, a C.sub.1-6 alkylsulfonyl-carbamoyl group, a phosphoric acid residue optionally esterified by a C.sub.1-6 alkyl group, R.sup.AO--C(.dbd.O)-- (R.sup.A is as defined above) or a 5- or 6-membered heterocyclic residue having 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (said heterocyclic residue is optionally substituted by an oxo group), R.sup.3 and R.sup.4 are the same or different and each is a hydrogen atom, a cyano group, a halogen atom, a C.sub.1-6 alkyl group or a C.sub.1-6 alkoxy group, R.sup.5 is a C.sub.1-6 alkyl group or a C.sub.3-6 cycloalkyl group, R.sup.6 is a hydrogen atom or R.sup.C (wherein R.sup.C is a C.sub.1-7 acyl group optionally substituted by a carboxyl group), R.sup.7, R.sup.8 and R.sup.9 are the same or different and each is a hydrogen atom, a C.sub.1-6 alkyl group, a C.sub.2-4 alkenyl group, a halogen atom, a halo C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a halo C.sub.1-6 alkoxy group, or a carboxyl group, or the adjacent R.sup.7 and R.sup.8 are joined to form --CH.dbd.CH--CH.dbd.CH--, provided that (1) when ring A is a group of the formula (a) and R.sup.1 is a C.sub.1-6 alkyl group, then R.sup.6 is R.sup.C, (2) when ring A is a group of the formula (b) and R.sup.2 is a carboxyl group or a C.sub.1-6 alkoxy-carbonyl group, then R.sup.7 is a C.sub.2-4 alkenyl group, (3) when ring A is a group of the formula (b) and R.sup.2 is a hydroxycarbamoyl group, then R.sup.3 is a hydrogen atom, or (4) when ring A is a group of the formula (a), R.sup.1 is R.sup.AO--C(.dbd.O)--X--(O)n- and X is ##STR00137## then n is 0. 6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1, an optically active form thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. 7. A method for treatment of osteoporosis, which comprises administering an effective amount of a compound according to claim 1, an optically active form thereof, or a pharmaceutically acceptable salt thereof to a patient in need thereof. 8. The method of claim 7, wherein said compound according to claim 1, optically active form thereof or pharmaceutically accepteable salt thereof is administered in combination with other therapeutic drug for osteoporosis. 9. The method of claim 8, wherein said other therapeutic drug for osteoporosis is selected from the group consisting of a calcium agent, a vitamin D preparation, a vitamin K preparation, a female hormone preparation, an estrogen antagonist preparation, a anabolic steroid preparation, a parathyroid hormone preparation, a calcitonin preparation, a bisphosphonate preparation and an ipriflavone preparation. 10. A compound according to claim 1, an optically active form thereof, or a pharmaceutically acceptable salt thereof having calcium receptor antagonist activity evidenced by an IC.sub.50 concentration of less than 1 .mu.M.

Details for Patent 7,285,572

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2023-05-28