Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
1995-12-28
2002-02-12
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C549S005000, C549S009000
Reexamination Certificate
active
06346521
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an optically active benzothiepin derivative possessing osteogenesis-promoting activity, bone resorption-suppressing activity and other activities, and a bone disease prophylactic or therapeutic agent comprising it as an active ingredient.
BACKGROUND OF THE INVENTION
Bone disease is a pathologic state or disease involving some symptom or risk due to quantitative reduction in bone exceeding a specified amount. Major symptoms of osteoporosis, a bone disease, are for example, spinal kyphosis, and fractures of dorsolumbar bones, vertebral centra, femoral necks, lower end of radius, ribs, and upper end of humerus. In healthy bone tissue, bone destruction occurs continuously, with a good balance between bone formation and resorption. Osteoblasts and osteoclasts, respectively, play key roles in bone formation and resorption. Deterioration of the balance therebetween results in quantitative reduction in bone. Traditionally, bone resorption suppressors, such as estrogens, calcitonin and bisphos-phonates, have been primarily used to prevent and treat osteoporosis. However, these bone resorption suppressors fail to achieve satisfactory effect in some cases, due to limitations of the subject or to uncertain efficacy.
Alternatively, the present inventors have discovered a sulfur-containing heterocyclic compound possessing excellent bone resorption-suppressing activity, a compound represented by the following general formula (A) or (B), or a salt thereof (Japanese Pat. Unexamined Publication Nos. 232880/1991 and 364179/1992).
wherein ring A is a benzene ring that may be substituted; R represents a hydrogen atom or a hydrocarbon group that may be substituted; B represents a carboxyl group that may be esterified or amidated; X represents —C H(OH)— or —CO—, k represents 0 or 1, k′ and n each represent 0, 1 or 2.
An example of such a compound is a compound represented by formula (C):
has been described.
There is a need for the development of a prophylactic or therapeutic agent having improved properties (stability, absorbability, bioavailability etc.) for clinically useful pharmaceuticals (especially oral preparations).
SUMMARY OF THE INVENTION
The present inventors conducted intensive investigation to develop a clinically more useful drug that has direct action on the bone, suppresses bone resorption, and promotes bone formation, and for the first time synthesized an optically active benzothiepin derivative represented by formula (I):
wherein R represents a lower alkyl group; R
1
and R
2
independently represent a lower alkyl group, or may bind together to form a ring; and found that this compound is unexpectedly very useful clinically among the compounds represented by formula (A) or (B) above, and is particularly effective in osteogenesis-promoting activity and oral absorbability etc. For example, the optically active benzothiepin derivative of the formula (I) is superior to the compound of the formula (C) in oral absorbability. The present inventors conducted further investigation based on this finding, and developed the present invention.
Accordingly, the present invention relates to:
(1) An optically active compound of the formula (I):
wherein R represents a lower alkyl group; R
1
and R
2
independently represent a lower alkyl group, or together represent a lower alkylene,
(2) A compound according to the above (1), wherein R, R
1
and R
2
independently are a C
1-4
alkyl group,
(3) A compound according to the above (1), which is (2R,4S)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide,
(4) A method of producing an optically active compound of the formula (I):
wherein R represents a lower alkyl group; R
1
and R
2
independently represent a lower alkyl group, or may bind together to form a ring, by reacting an optically active compound of the formula (II):
wherein R is defined as noted above, or its derivative reactive or salt at the carboxyl group, with a compound of the formula (III):
wherein R
1
and R
2
are defined as noted above, or its derivative reactive or salt at the amino group,
(5) An optically active compound of the formula (II):
wherein R represents a lower alkyl group, or its derivative reactive or salt at the carboxyl group,
(6) An osteogenesis promoter comprising an optically active compound of the formula (I) according to the above (1),
(7) An osteogenesis promoter according to the above (6), which is orally absorbable,
(8) A prophylactic or therapeutic agent for bone diseases comprising an optically active compound of the formula (I) according to the above (1),
(9) A promoter for cure of bone fracture comprising an optically active compound of the formula (I) according to the above (1),
(10) A method of promoting osteogenesis in a mammal which comprises administering to said mammal in need an effective amount of an optically active compound of the formula (I) according to the above (1),
(11) A method of preventing or treating bone diseases in a mammal which comprises administering to said mammal in need an effective amount of an optically active compound of the formula (I) according to the above (1),
(12) A method of promoting cure of bone fracture in a mammal which comprises administering to said mammal in need an effective amount of an optically active compound of the formula (I) according to the above (1),
(13) Use of an optically active compound of the formula (I) according to the above (1) for the manufacture of an osteogenesis promoter,
(14) Use of an optically active compound of the formula (I) according to the above (1) for the manufacture of a prophylactic or therapeutic agent for bone diseases, and
(15) Use of an optically active compound of the formula (I) according to the above (1) for the manufacture of a promoter for cure of bone fracture.
With respect to the above formulas, the lower alkyl group represented by R, R
1
or R
2
is exemplified by straight chain or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl. R
1
and R
2
may represent together a lower alkylene, in which case
may represent
(n represents an integer from 2 to 4).
Preferably, R, R
1
and R
2
are each an alkyl group having 1 to 4 carbon atoms, such as methyl or ethyl.
The compound (I) of the present invention, an optically active compound of the (2R,4S) configuration, preferably contains substantially no compounds of the (2S,4R) configuration, and has an optical purity of nearly 100%.
Of the compounds of formula (I), (2R,4S)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide etc. are preferred.
Compound (I) is produced by reacting an optically active compound represented by formula (II), or its derivative reactive or salt at the carboxyl group, with a compound represented by formula (III), or its derivative reactive or salt at the amino group.
Preferable derivatives of compound (III) reactive at the amino group thereof include Schiff's base type imino or enamine form tautomeric isomers resulting from reaction of compound (III) and a carbonyl compound such as aldehyde (e.g., acetaldehyde) or ketone (e.g., acetone); silyl derivatives resulting from reaction of compound (III) and a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide or bis(trimethylsilyl)urea; and derivatives resulting from reaction of compound (III) and phosphorus trichloride or phosgene.
Preferable derivatives of compound (II) reactive at the carboxyl group thereof include acid halides, acid anhydrides, activated amides and activated esters, all obtained by conventional methods. More specifically, such preferable reactive derivatives include acid chlorides; acid azides; mixed acid anhydrides such as those with a substitutional phosphoric acid such as dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dib
Oda Tsuneo
Sohda Takashi
Taketomi Shigehisa
Lambkin Deborah C.
Takeda Chemical Industries Ltd.
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