WO2004031125A1 - スピロ化合物、それを含有する医薬組成物及び該化合物の中間体 - Google Patents
スピロ化合物、それを含有する医薬組成物及び該化合物の中間体 Download PDFInfo
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- WO2004031125A1 WO2004031125A1 PCT/JP2003/004889 JP0304889W WO2004031125A1 WO 2004031125 A1 WO2004031125 A1 WO 2004031125A1 JP 0304889 W JP0304889 W JP 0304889W WO 2004031125 A1 WO2004031125 A1 WO 2004031125A1
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
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- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
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- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/24—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system containing rings other than six-membered aromatic rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/93—Spiro compounds
- C07C2603/95—Spiro compounds containing "not free" spiro atoms
- C07C2603/96—Spiro compounds containing "not free" spiro atoms containing at least one ring with less than six members
- C07C2603/97—Spiro compounds containing "not free" spiro atoms containing at least one ring with less than six members containing five-membered rings
Definitions
- the present invention relates to a novel spiro compound that acts as a selective estrogen receptor module, more specifically, a spiro [indene-1,1,1-indane] derivative and a related compound, a pharmaceutical composition containing the same, and It relates to an intermediate of the compound.
- HRT hormone replacement therapy
- ERT estrogen replacement therapy
- SERMs selective estrogen receptor modules
- Raloxifene hydrochloride Acts as an estrogen agonist on lipid metabolism, but acts as an estrogen antagonist on reproductive systems such as the uterus and breast.
- moxifene citrate also acts as an estrogen agonist on bone and lipid metabolism, as does raloxifene hydrochloride, and acts as an estrogen antagonist on the breast, but unlike raloxifene on the uterus. Acts as a partial agonist.
- Such a difference in the action characteristics depends on the chemical structure of each drug, and this is considered to be based on a difference in the structure of the compound-receptor complex. This means that new SERMs with different action characteristics can be created.
- SERMs act as estrogen agonists for tissues where estrogen action is expected, and at the same time act as estrogen antagonists for tissues where estrogen action is not desirable.
- the use of such SERMs can alleviate the estrogen deficiency symptoms while preventing or treating the occurrence of breast cancer and endometrial cancer.
- SERMs currently in clinical use are not sufficiently satisfactory as such ideal SERMs.
- raloxifene hydrochloride moxifen reduces the incidence of breast cancer, has a preventive and therapeutic effect on postmenopausal osteoporosis, and has an effect of improving lipid metabolism.
- WO 98/02151 discloses that a compound represented by the following formula is a chemokine receptor and an anthrone gonist, and is useful as a therapeutic drug for diseases associated with abnormally increased and / or activated leukocytes. It is said that there is. However, there is no description in this document regarding its usefulness as SERM.
- R 50 and R 51 are independently 1 OH, halogen, etc.
- R 52 and R 53 independently represent 1 H, an aliphatic group, a substituted aliphatic group, a halogen, 1 NH 2 , -NH (aliphatic group), 1 NH (substituted aliphatic group), 1 N (aliphatic group) ) 2 or-N (substituted aliphatic group) 2 It is. ]
- WOO 2/46134 describes that a 1,, 3,3,1-tetrahydro-1,2,2′-spirobi (2H-indene) derivative represented by the following formula is an estrogen receptor ligand. .
- ⁇ ⁇ ⁇ and Ri? are the same or different and are groups selected from hydroxyl, RA or OR A ,
- RA is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl,
- X is a methylene group (one CH 2 —), an ethylene group (one CH 2 CH 2 —), or a substituted methylene group (—CR B H—), wherein R B is ( ⁇ 4 alkyl group;
- R 4 is a hydrogen atom or the like
- R 5 , R 6 , R 5 , and R 6 are the same or different and are a hydrogen atom, a hydroxyl group, or the like.
- the estrogen receptor ligand is a compound that forms a spiro bond at the second position of each of indane and indane, or at the second position of each of 1,2,3,4-tetrahydronaphthylene with indane. And the chemical structure is different from the compound of the formula (I) described below.
- the above compound forms a spiro bond at the 2-position of indane, and further has a 2-piperidinoethoxy group in the benzene ring portion of indane, and thus has a different chemical structure from the compound of the following formula (I).
- R 11 R 12 , R 13 and R 14 are each independently selected from the group consisting of H, R b , OR b and the like;
- R 5 is selected from the group consisting of H, F and alkyl
- R a is selected from the group consisting of H, Ci-e alkyl and e- acyl;
- R b is H, it is selected from alkyl and ( ⁇ _ of 6 Ashiru group, ⁇ A alkyl and Ashiru wherein the groups may be substituted with R e groups;
- R e is selected from the group consisting of ⁇ R d and NR d R e,
- R d and R ⁇ are each independently R 5 is selected from the group consisting of ⁇ and C i — 7 alkyl; Alternatively R d and R e may form a nitrogen atom and connexion 4-8 membered ring such together connecting them, 0 ⁇ 's one wherein, NH, are interrupted by NCH 3 and S And the ring may be substituted with 1, 2, 3 or 4 alkyl groups or 1 or 2 R f groups;
- the present inventors have found that by acting as an estrogen antagonist on the reproductive system such as the uterus and breast, and as an estrogen agonist on lipid metabolism, bone, cardiovascular and brain, breast cancer To prevent or treat postmenopausal lipid metabolism disorders and osteoporosis while preventing or treating the onset of cancer and endometrial cancer, and to improve menopausal symptoms that could not be achieved by conventional SERM As a result of intensive studies to provide a more useful SERM that can be performed, the inventors have found that a spiro compound represented by the formula (I) described below meets this purpose, and completed the present invention.
- the present invention is as follows.
- 1 ⁇ and 1 2 are the same or different, a hydrogen atom, a fluorine atom, a chlorine atom or a
- Ci— represents a 6 alkyl group
- n 1, 2 or 3
- a bond containing a broken line represents a single bond or a double bond
- A is— (CH 2 ) P— N (R 3 ) (R 4 ); — X— (CH 1 N (R 3 ) (R 4 );
- X represents an oxygen atom or a zeo atom
- R 3 and R 4 are the same or different, Ci 6 alkyl or Hue sulfonyl ⁇ 1 - 4 alkyl group, or R 3 and R 4 are such together with the adjacent nitrogen atom connexion, CI- e Forming a piperidine ring, piperidine ring, homopiperidine ring, piperazine ring or morpholine ring, each of which may be substituted with one or two groups selected from alkyl, phenyl and benzyl. May be
- R 5 represents an alkyl group, C 3 8 cycloalkyl group or a C 3 _ 8 cycloalkyl (4 ⁇ alkyl group,
- R 6 represents a hydrogen atom or a C _ 4 alkyl group
- r, s and t each independently represent 1 or 2.
- R 31 and R 41 together with the adjacent nitrogen atom form a pyrrolidine ring, a piperidine ring or a homopiperidine ring, each of which may be substituted with one or two methyl groups.
- R 31 and R 41 together with an adjacent nitrogen atom form a pyrrolidine ring, a piperidine ring or a homopiperidine ring which may be substituted with one or two methyl groups.
- (1R *, 3 S *) 3— [4— (2-Piberidinoethoxy) phenyl] -1,1,1 ′ —spirobiindane-1,5, -diol or its pharmaceutically acceptable Acid salt.
- a pharmaceutical composition comprising, as an active ingredient, the compound according to any one of the above [1] to [7] or a pharmaceutically acceptable acid addition salt thereof.
- composition according to the above [8] or [9] and the pharmaceutical composition can, or should be, used for the prevention or treatment of osteoporosis, climacteric symptoms or breast cancer.
- a commercial package comprising a description of the pharmaceutical composition which states that
- n 1, 2 or 3
- X represents an oxygen atom or a zeo atom
- R 3 and R 4 are the same or different and each represents a Ci- 6 alkyl group or a phenyl Ci_ 4 alkyl group, or R 3 and R 4 are taken together with an adjacent nitrogen atom to form a Ci-e alkyl, phenyl And a pyridine ring, a piperidine ring, a homopyridine, a piperazine ring or a morpholine ring which may be substituted with one or two groups selected from benzyl and benzyl. ,
- R 5 is C _ 6 alkyl group, C 3 _ 8 cycloalkyl group or a C 3 _ 8 cycloalkyl C - represents 4 ⁇ alkyl group,
- R 6 represents a hydrogen atom or a C 4 alkyl group
- r, s and t each independently represent 1 or 2.
- n 1, 2 or 3.
- An object of the present invention is to provide a spiro compound useful as a SERM.
- an object of the present invention is to provide a compound having high utility as prevention and / or treatment of osteoporosis, climacteric symptoms and breast cancer.
- Another object of the present invention is to provide a pharmaceutical composition containing the compound.
- Still another object of the present invention is to provide an intermediate for producing the compound.
- a spiro compound represented by the following formula (I) or a pharmaceutically acceptable acid addition salt thereof hereinafter, also referred to as “the compound of the present invention”.
- R 1 and R 2 are the same or different and each represent a hydrogen atom, a fluorine atom, a chlorine atom, or a ( ⁇ alkyl group;
- n 1, 2 or 3
- a bond containing a broken line represents a single bond or a double bond
- A is one (CH 2 ) P — N (R 3 ) (R 4 ); one X— (CH 2 ) q — N (R 3 ) (R 4 );
- X represents an oxygen atom or a zeo atom
- R 3 and R 4 may be the same or different and each represents — 6 alkyl group or phenyl ( 4 alkyl group, or R 3 and R 4 together with an adjacent nitrogen atom; — 6 alkyl, phenyl and A piperidine ring, a piperidine ring, a homopiperidine ring, a piperazine ring or a morpholine ring which may be substituted with one or two groups selected from
- R 5 is C i 6 alkyl group, C 3 8 cycloalkyl group or a C 3 _ 8 cycloalkyl - represents a 4 ⁇ alkyl group,
- R 6 represents a hydrogen atom or a C i _ 4 alkyl group
- r, s and t each independently represent 1 or 2.
- Pharmaceutically acceptable acid addition salts of the compounds represented by formula (I) include, for example, inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and the like. Salt, oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p — Organic acid salts such as toluenesulfonate and trifluoromethanesulfonate; and amino acids such as glutamate and bisparaginate.
- inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and the like. Salt, oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p —
- the spiro carbon atom of the compound of formula (I) is an asymmetric carbon atom.
- the compound of the formula (I) may further have one or more asymmetric carbon atoms. Further, the compound of the formula (I) may cause geometric isomerism.
- the compounds of formula (I) may exist as several stereoisomers (eg, optically active, diastereoisomeric, etc.). these And mixtures and racemates thereof are included in the compounds of the present invention.
- the compound of the present invention is a compound that forms a spiro bond at the 1-position of indane or indene, a position number is given as shown in the following formula.
- the compounds of the present invention are named according to the position numbers.
- alkyl group may be linear or branched, and specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, 2-ethylbutyl and equivalents thereof.
- "( ⁇ Alkyl group)" means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isoptyl group, a sec-butyl group or a tert-butyl group.
- ⁇ 3 _ 8 cycloalkyl group examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and a heptyl group and Shikurookuchiru group cyclohexylene.
- C 3 8 cycloalkyl 4 alkyl group refers to being replacement by "c 3 _ 8 cycloalkyl group”"( ⁇ 4 alkyl group", for example, cyclopropylmethyl group, shea click port Examples include a pentylmethyl group, a cyclohexylmethyl group and their equivalents.
- phenylalkyl group means a “( ⁇ alkyl group) substituted with a phenyl group, and includes, for example, a benzyl group, a phenyl group, a phenylpropyl group and equivalents thereof.
- the compound of the formula (I) in which the bond containing the broken line is a single bond is the compound of the following formula (1-1) in which the bond at the 2-position and the 3-position is a single bond.
- the bond containing the broken line is a double bond
- the compound of the formula (I) is a compound represented by the following formula (I-2) in which the bond at the 2-position and the 3-position is a double bond.
- those compounds which show good SERM action are those wherein A in the formula (I) is —X— (CH 2 ) q —N (R 3 ) (R 4 ) or the following formula (a ,)
- A is —X— (CH 2 ) q —N (R 3 ) (R 4 ), and RR 2 , R 3 ⁇ RX, n, q and the bond including the broken line are the same as those described above. Certain spiro compounds or pharmaceutically acceptable acid addition salts thereof are even more preferred. '
- A is -0— (CH 2 ) q — N (R 3 ) (R 4 ), n is 1, ⁇ R ⁇ RR 4 , q and the bond including the broken line are the same as described above.
- the spiro compound or a pharmaceutically acceptable acid addition salt thereof is more preferable.
- 1 ⁇ and 1 2 are the same or different, a hydrogen atom, a full Uz atom or a chlorine atom, A is - 0- ( CH 2) a 2 one n (R 3 °) (R 4Q), n is 1, R 3 ° and R 4 ° are the same or different, alkyl group, or R 3G and R 4Q May form, together with the adjacent nitrogen atom, a pyrrolidine ring, a piperidine ring or a homopiperidine ring which may be substituted with one or two alkyls.
- Is a single bond or a double bond, or a pharmaceutically acceptable acid addition salt thereof.
- Particularly preferred compounds include a spiro compound represented by the following formula (I-1a) or (I-2a) or a pharmaceutically acceptable acid addition salt thereof.
- R 31 and R 41 together with the adjacent nitrogen atom form a pyrrolidine ring, a piperidine ring or a homopiperidine ring, each of which may be substituted with one or two methyl groups.
- particularly preferred compounds include, for example, the following spiro compounds or pharmaceuticals thereof. And acid addition salts which are acceptable.
- 1 ⁇ and 1 ⁇ 2 are the same or different and represent a hydrogen atom, a fluorine atom, a chlorine atom or a Ci-e alkyl group,
- n 1, 2 or 3
- X represents an oxygen atom or a zeo atom
- R 5 is C i-6 alkyl group, C 3 _ 8 cycloalkyl group or a C 3 - represents an 8 cycloalkyl C i-4 ⁇ alkyl group,
- R 6 represents a hydrogen atom or a C i _ 4 alkyl group
- r, s and t each independently represent 1 or 2.
- n 1, 2 or 3.
- the compound of the formula (I) can be produced, for example, by the following production method.
- the hydrogenation reaction is carried out by reacting the compound of the formula (1-2) with hydrogen in a suitable solvent in the presence of a catalyst under normal pressure or pressure.
- a catalyst include palladium carbon, palladium hydroxide carbon, platinum, rhodium carbon and the like.
- a solvent examples include alcohols such as methanol, ethanol, isopropanol and butanol, ethyl acetate, dimethylformamide, N-methylbiperidone, and acetic acid.
- the reaction temperature is usually 0 ° C;
- diastereomers are formed by this method, they should be isolated and purified by conventional methods such as chromatography, recrystallization, and reprecipitation.
- the compound having a bond containing a broken line is a double bond, that is, the compound of the formula (I 2) is represented by the following formula (II-1)
- This demethylation is carried out by reacting the compound of the formula (II-1) with lithium diphenylphosphine in a suitable solvent.
- a suitable solvent for reacting the compound of the formula (II-1) with lithium diphenylphosphine.
- lithium diphenylphosphine boron tribromide, sodium ethyl thiolate, pyridine / hydrochloride complex, ethanethiol Z aluminum chloride and the like can be used.
- the solvent to be used include dimethoxyethane, diglyme, tetrahydrofuran, ethers such as 1,4-dioxane, hydrocarbons such as toluene and xylene, chloroform, dichloromethane, 1,2-dichloroethane, and the like.
- reaction temperature is usually 0 ° C to 200 ° C, preferably 20 ° C to 100 ° C.
- the compound of the formula (II-1) is a compound of the formula (II-1) and a compound of the following formula (IV-1)
- M represents Li or MgBr, UKR 2 and ⁇ represent the same as described above
- a suitable solvent reacted in a suitable solvent, followed by the reaction in the presence of an acid catalyst. It can be produced by a dehydration reaction in a suitable solvent.
- the solvent for this reaction for example, getyl ether, tetrahydrofuran, toluene, xylene, 1,2-dichlorobenzene can be used as appropriate. These solvents may be used alone or as a mixture of two or more.
- the acid catalyst include p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, and hydrochloric acid.
- the dehydration reaction proceeds usually at 0 ° C to 150 ° C, preferably at 80 ° C to 120 ° C.
- alkyl lithium include n-butyl lithium, sec-butyl lithium, and tert-butyl lithium.
- the reaction between the compound of the formula (IV-2) and the alkyl lithium, and the reaction between the compound of the formula (IV-1) and the compound of the formula (III) are usually performed at a temperature of -100 ° C to 120 ° C, preferably _80 ° C. Proceed at ⁇ 0 ° C.
- the solvent for example, tetrahydrofuran, toluene, and ethyl ether can be appropriately used.
- the reaction of the compound of the formula (IV-2) with metallic magnesium can be carried out according to a Grignard reaction in a conventional manner. Specific examples are shown in Examples D to F.
- the compound of the formula (III) can be produced from a compound of the following formula (V) which is commercially available or a compound known per se by the following method. 4889
- n the same as described above.
- Step 1 The compound of the formula (VI I) can be produced by reacting the compound of the formula (V) with the compound of the formula (VI) under the reaction conditions of a Grignard reaction generally performed.
- the compound of the formula (VI) is commercially available or is a compound known per se.
- 2- (2-bromo-5-methoxyphenyl) -1,4,4-dimethyl-4,5-dihydrooxazole is used as a raw material in J. Med. . Chem., 19, 1315 ( 1976) and J. Org. Chem. 3 40, can be prepared according to the method described in 1427 (1975).
- Step 2 The compound of the above formula (VI II) is reacted with a sulfuric acid aqueous solution of the compound of the formula (VI I) in a suitable solvent, preferably in a solvent of an ether such as 1,4-dioxane or diglyme. It can be manufactured by doing.
- Step 3 The compound of the above formula (IX) can be produced by subjecting the compound of the formula (VIII) to a hydrogenation reaction in the same manner as in the above-mentioned production method (A1).
- Step 4 The compound of the above formula (X) can be prepared by using the compound of the formula (IX) as a raw material. Can be produced according to the method of producing ketoesters from the carboxylic acids obtained.
- Step 5 The compound of the above formula (XI) can be produced by using the compound of the formula (X) as a starting material and diazotizing the a-position of the ketoester according to a conventional method.
- Step 6 The compound of the formula (III) is reacted with rhodium (II) acetate according to the method described in J. Amer. Chem. Soc, 107, 196 (1985). Can be manufactured. Specific examples are shown in Examples A to C.
- the compound of the formula (IV-2) is a commercially available compound, or a method known per se, a method described in the following production methods (C1) to (C4), or produced according to these methods be able to.
- n 1 in the above formula (III) is prepared by subjecting 5,5'-dimethoxyspirobero 1,1,1 indane to acidification according to the method described in Tetrahedron Lett., 28, 3131 (1987). Can also be manufactured. 5, 5'-dimethoxy spirobifluorene one 1, 1 '-.... Indane Bull Chem Soc Jpn, can be prepared by the method described in 4 3 496 (1971).
- This dehydration condensation is achieved by a Mitsunobu reaction, that is, by reacting a compound of the formula (II-I), a compound of the formula (XII) or the formula (XIII), triphenylphosphine and an azodicarboxylic acid diester.
- This reaction can be carried out by the usual method of the Mitsunobu reaction or a method analogous thereto. Specific examples are shown in Example L and Example M.
- the compound of the above formula (I1-2) can be produced by removing the aryl group of the compound of the following formula (I1-3) according to a conventional method. Specific examples are shown in Examples H and K.
- n the same as described above.
- the compound of formula (I1-3) is prepared from the compound of formula (III) and p-aryloxypromobenzene according to the method described in the production method of intermediate (B1). Can be manufactured.
- the present example is shown in Example G.
- the reaction between the compound of the formula (I 1-4) and the compound of the formula (XIV) is carried out under anhydrous conditions in the presence of a palladium catalyst, a phosphorus ligand and a base.
- a palladium catalyst examples include 1,4-dioxane, tetrahydrofuran, toluene, dimethylformamide and the like.
- Palladium acetate or palladium chloride is used as the palladium catalyst, and the phosphorous ligands are 2- (di-tert-butylphosphino) biphenyl, diphenylphosphinophenol, 2- (diphenylphosphino) -1,1,1, -Use binaphthyl or the like.
- the base tripotassium phosphate, sodium tert-butoxide and cesium carbonate can be used.
- the reaction temperature is usually from 60 ° C to 150 ° C.
- the compound of the formula (I 1-4) can be prepared by combining the compound of the formula (I 1-2) with 2- [N, N-bis (trifluoromethylsulfonyl) amino] in a suitable solvent in the presence of a base. It can be produced by reacting with pyridine, trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride. Examples of the base to be used include sodium hydride, triethylamine, potassium carbonate, sodium carbonate, pyridine, and 2,6-lutidine.
- Examples of the solvent include toluene, xylene, dimethoxyethane, 1,2-dichloroethane, acetone, methylethylketone, 1,4-dioxane, diglyme, ethyl acetate, dimethylformamide, and dimethylsulfo. Oxide and pyridine.
- the reaction temperature is usually from 100 to 150 ° C, preferably from 20 to 70 ° C. A specific example is shown in Example N.
- the compound of the formula (XIV) is commercially available or can be produced by a method known per se.
- the compound of the above formula (XV) and the compound of the above formula (XVI) are reacted in a suitable solvent in the presence of a base.
- a base for example, sodium hydride, sodium hydroxide, potassium hydroxide, or the like is used.
- solvent for example, dimethyl sulfoxide, dimethylformamide, toluene, xylene, 2-propanol, or the like can be used as appropriate.
- the reaction temperature is usually 0 to 150 ° C, preferably 60 to 120 ° C.
- the compounds of the formulas (XV) and (XVI) are commercially available or can be synthesized by a method known per se.
- the compound of the above formula (XIX) is prepared by condensing a carboxylic acid of the formula (XVI I) with a secondary amine of the formula (XVI II) in a suitable solvent in the presence of a dehydrating condensing agent.
- a dehydrating condensing agent Alternatively, it can be produced by converting the compound of the formula (XVI I) into the corresponding acid chloride by a conventional method, and then subjecting it to a condensation reaction with the compound of the formula (XVI II) in a suitable solvent in the presence of a base.
- dehydrating condensing agent examples include ⁇ , ⁇ ′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, ⁇ , ⁇ , carbonyldiimidazole, ⁇ , ⁇ , 1-carbodidisuccinic imide, 1-ethoxycarboryl 2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl azide, propanephosphonic anhydride, benzo'triazole-11-yloxysitol (dimethyl (Amino) phosphonium'hexafluorophosphate is used.
- the base for example, pyridine, sodium hydroxide, potassium carbonate, sodium hydrogen carbonate and the like are used.
- solvent for example, dichloromethane, tetrahydrofuran, water, toluene and the like can be appropriately used.
- the reaction temperature is usually from 150 to 150 ° C, preferably from 110 to 40 ° C.
- Compounds of formula (IV-2b) can be prepared by reacting a compound of formula (XIX) with a borane'tetrahydrofuran complex in tetrahydrofuran.
- the reaction temperature is usually -50 to 150 ° C, preferably 0 to 80 ° C.
- the compound of the following formula (IV-2c) can be obtained by converting a compound of the formula (XX) and a compound of the formula (XXI), which are known per se or obtained according to the production method thereof, according to the method of the production method (C2) It can be manufactured with the route shown in (1). Specific examples are shown in Reference Examples 3 to 5. Represents a loxyl group or a halogen atom, and R 6 , r and t represent the same as described above. )
- the compound of the following formula (IV-2d) can be produced by reacting the compound of the following formula (XXV) with a borane-tetrahydrofuran complex in tetrahydrofuran.
- the compound of the formula (XXV) can be produced by reacting a compound of the formula (XXIV) and a compound of the formula (XXIV) known per se or obtained according to a production method thereof according to a conventional method. Specific examples are shown in Reference Examples 6 and 7.
- the compound of the formula (I) produced by each of the above-mentioned production methods can be isolated and purified by a conventional method such as chromatography, recrystallization and reprecipitation.
- the compound of the formula (I) can be obtained in the form of a free base or an acid addition salt according to the type of the functional group present in the structural formula, the selection of the starting compound, and the reaction conditions. Can be converted to a compound.
- the compound (I) can be converted to an acid addition salt by treating it with various acids according to a conventional method.
- Various stereoisomers of the compound of the formula (I) can be separated and purified according to a conventional method such as chromatography.
- Test Example 1a Effect on menopausal symptoms (hot flash-like symptoms):
- Ovariectomized rats were prepared by removing bilateral ovaries of 8-week-old Jcl: SD female rats (CLEA Japan) under ether anesthesia. Animals were bred under lighting for 12 hours (6: 00-18: 00) at room temperature of 24 ⁇ 0.5 ° C, and were allowed to ingest solid feed (CE-2, manufactured by CLEA Japan) and water freely. . Rats 2 weeks after ovariectomy were subjected to the following experiment. The rats used for the sham operation group were treated similarly except for ovariectomy.
- the tail skin temperature of each rat was set to be anaesthetized according to the method of Hosono et al. (Am. J. Physiol. Regulatory Integrative Comp. Physiol. 280: 111341-M347, 2001). Measured. In other words, the temperature sensor is 5 cm from the light ridge.
- Test compound dose (mg / kg) Average tail skin temperature (c)
- Test compound Dose; mg / kg
- Average tail skin temperature (° C)
- Example 1 and Example 36A shown in Table 2 improved photoflash-like symptoms similarly to the estrogen receptor agonist /?-estradiol. Further, the combined effect of /?-Estradiol and the compound of the present invention shown in Table 3 was not significantly different from the effect of ⁇ -estradiol alone. That is, the compounds of Example 1 and Example 36A inhibit the effect of estradiol on tissues having hot flash-like symptoms. Did not harm.
- test compound was dissolved in a 10% aqueous solution of cyclodextrin and orally administered once daily to ovariectomized rats for 2 weeks, and blood was collected under ether anesthesia. Blood samples were allowed to clot at room temperature for 1 hour and serum was obtained after centrifugation at 3000 rpm for 10 minutes. The LH content in the serum was measured using a light LH radioimmune kit (manufactured by Imnotech, France). Table 4 shows the results.
- Rat test compound dose (mg / kg) Serum LH (ng) Pseudo #platinum solvent ⁇ 0.10 ⁇ 0.03
- Example 1 Ovariectomized rats and comparison with a solvent control group (Daneut's multiple test)
- the i-conjugate of Example 1 shown in Table 4 showed an increase in LH level due to ovariectomy similarly to? -Estradiol. Significantly suppressed. That is, the compound of Example 1 exhibits a favorable effect on hot flash-like symptoms, which is a climacteric symptom, like estrogen.
- Test Example 2 Effect of ovariectomy rat on decrease in femoral bone density:
- Rat used Test compound Dose (g / kg) Bone density (mg / cm 3 ) Sham operation rats Solvent 799.9 ⁇ 41.2
- Rat used Test compound dose (mg / kg) Bone density (mg / cm 3 )
- test compound was dissolved in a 10% aqueous solution of cyclodextrin and orally administered to a 7-week-old Jcl: SD male rat (manufactured by Nippon Clea) once a day for 4 consecutive days. Blood was collected the day after the last administration, and cholesterol in plasma was measured using a measurement kit (Cholesterol CII-Test Co., manufactured by Wako Pure Chemical Industries, Ltd.). The results are shown in Table 6 (1) and Table 6 (2). Table 6 (1)
- Test compound dose (mg / kg) Blood cholesterol (mg / dl)
- Test compound dose (mg / kg) Blood cholesterol (mg / dl)
- test compound was continuously orally administered to ovariectomized and sham-operated rats in the same manner as in Test Example lb, and then the uterus was excised and its weight was measured.
- Rat used Test compound Dose (mg / kg) Uterine weight (mg) Pseudo «Late solvent 574.0 ⁇ 36.3
- Rat used Test compound Dose; mg / kg) Uterine weight (mg)
- Example 1 Comparison with the group administered with ⁇ -estradiol alone (Student's t-)
- the compound of Example 1 shown in Table 7 does not significantly increase the child weight of ovariectomized rats unlike one estradiol.
- the compound of Example 1 significantly inhibited the carotenoid weight-increasing effect of / -estradiol, that is, the compound of Example 1 did not show any uterine-related side effects.
- the compound of formula (I) improves the climacteric symptoms (hot flash-like symptoms) exhibited by ovariectomized rats, prevents the femoral bone density of ovariectomized rats from decreasing, Since it has a lipid-lowering effect and does not change the weight of the uterus in the ovariectomized rat, diseases associated with estrogen, such as climacteric symptoms, osteoporosis, cartilage degeneration, endometriosis, feminization Prevention and prevention of breast, obesity, hyperlipidemia, atherosclerotic disease, incontinence, autoimmune disease, breast cancer, endometrial cancer, colon cancer, lung cancer, prostate cancer, memory impairment, cognitive impairment, dementia, etc. / Or useful for treatment.
- compounds of formula (I) are useful for osteoporosis, menopause It can be expected as a prophylactic and / or therapeutic agent for symptoms and breast cancer.
- the administration route of the compound of the formula (I) may be any of oral administration, parenteral administration, rectal administration and transdermal administration.
- the dosage varies depending on the administration method, patient symptoms, patient age, treatment type (prevention or treatment), etc., but is usually from 0.0 :! to 4 Omg / kg / day, preferably 0; ! ⁇ 2 O mg / kg / day.
- the compound of formula (I) is usually administered in the form of a pharmaceutical composition prepared by mixing with a pharmaceutical carrier.
- a pharmaceutical carrier of the pharmaceutical composition a substance which is commonly used in the field of pharmaceutical preparations and which does not react with the compound of the formula (I) is used.
- Dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, injections, ointments, patches and the like. These preparations are prepared according to a conventional method. In the case of liquid preparations, they may be dissolved or suspended in water or other suitable medium at the time of use. Tablets and granules may be coated by a known method. In the case of an injection, the compound of formula (I) is prepared by dissolving the compound of formula (I) in water, but may be dissolved using an isotonic agent or a solubilizing agent if necessary. Agents, buffers and preservatives Good.
- These preparations may contain the compound of the formula (I) in an amount of 0.01% or more, preferably 0.1 to 70%. These formulations may also contain other therapeutically active ingredients.
- the basic silica gel column chromatography used in Reference Examples and Production Examples is Chromatorex NH manufactured by Fuji Silicon Chemicals.
- This oily substance was dissolved in 5 OmL of toluene, 0.2 g of p-toluenesulfonic acid was added, and the mixture was heated under reflux for 15 hours using a Dean-Stark apparatus. The reaction solution was washed sequentially with 10 mL of water and 2 OmL of saturated saline, and concentrated under reduced pressure to obtain an oily substance.
- This oily substance was dissolved in 75 OmL of a 90% aqueous solution of dimethyl sulfoxide, and heated at 150 ° C for 1 hour. After cooling, the reaction mixture was added to 1.5 L of water and stirred, and the precipitated crystal was collected by filtration. The crystals were washed with water and hexane, and then dried to obtain 65 g of the title compound.
- Example D The reaction was carried out in the same manner as in Example D using 4- (4-bromophenyl) -11-isobutylbiperazine instead of 1-promo-1- (2-piperidinoethoxy) benzene in Example D. To give the title compound.
- the title compound was synthesized from (1) 1-3- (4-hydroxyphenyl) -15,5,1-dimethoxyspiro [indene-1,1'-indane] by reaction and treatment in the same manner as in Example L.
- Table 9 shows the title compound's - ⁇ value.
- Table 10 shows ⁇ -NMR spectra of the title compound.
- Table 11 shows 3 ⁇ 4-NMR data of the title compound.
- Example 36 The oily substance obtained in Example 36 was subjected to basic silica gel column chromatography (ethyl acetate hexane) to give 0.17 g of the free base of the title compound as an oily substance. This was dissolved in water-containing methanol, hydrochloric acid was added, and then lyophilized to form a hydrochloride.
- Example 36 The oily substance obtained in Example 36 was subjected to basic silica gel column chromatography (ethyl acetate / hexane) to give the free base of the title compound (0.01 g) as an oily substance. This was dissolved in water-containing methanol, hydrochloric acid was added, and then lyophilized to form a hydrochloride.
- Elemental analysis (monohydrochloride 3/4 hydrate): Theory C: 71.56; H: 6.71; N: 2.78; C1; 7.04: Theory C: 71.64; H: 6.65; N: 2.83; C1; 7.05
- reaction solution was filtered and washed with ethyl acetate.
- the filtrate and the washings were combined, concentrated, and the residue was subjected to a basic silica gel column chromatography (ethyl acetate / hexane) to obtain 0.28 g of the title compound as an oil.
- the compound of formula (I) acts as an estrogen antagonist on the reproductive system, such as the child and breast, as in the existing SERM, and has a role in lipid metabolism, bone, cardiovascular, and brain. Has an estrogen agonist effect. Furthermore, since the compound of the formula (I) has an effect of improving climacteric symptoms, it is superior to existing SERMs in preventing and / or treating osteoporosis and climacteric symptoms, or in preventing and treating breast cancer. Can be expected as a medicine. This application is based on a patent application No. 2002-289187 filed in Japan, the contents of which are incorporated in full herein.
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Priority Applications (7)
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JP2004541201A JPWO2004031125A1 (ja) | 2002-10-01 | 2003-04-17 | スピロ化合物、それを含有する医薬組成物及び該化合物の中間体 |
MXPA05003446A MXPA05003446A (es) | 2002-10-01 | 2003-04-17 | Compuestos espiro, composiciones medicinales que contienen los mismos, e intermediarios de los compuestos. |
AU2003227412A AU2003227412A1 (en) | 2002-10-01 | 2003-04-17 | Spiro compounds, medicinal compositions containing the same and intermediates of the compounds |
BR0315009-7A BR0315009A (pt) | 2002-10-01 | 2003-04-17 | Espirocompostos, composições medicinais que os contêm e intermediários desses compostos |
CA002500869A CA2500869A1 (en) | 2002-10-01 | 2003-04-17 | Spiro compounds, medicinal compositions containing the same and intermediates of the compounds |
EP03717627A EP1559707A4 (en) | 2002-10-01 | 2003-04-17 | SPIRO COMPOUNDS, MEDICINAL COMPOSITIONS CONTAINING THE SAID COMPOUNDS AND INTERMEDIATES THEREOF |
US10/529,601 US20050256308A1 (en) | 2002-10-01 | 2003-04-17 | Spiro compounds, medicinal compositions containing the same and intermediates of the compounds |
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JP2016029101A (ja) * | 2009-06-16 | 2016-03-03 | アンドルシェルシュ・インコーポレイテッド | 性ステロイド前駆体と選択的エストロゲン受容体モジュレーターとの組み合わせによるホットフラッシュ、血管運動症状及び寝汗の治療 |
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EP2900709B1 (en) * | 2012-09-25 | 2016-08-17 | 3M Innovative Properties Company | Rigid and contorted divinyl crosslinkers |
KR20160009624A (ko) | 2013-05-14 | 2016-01-26 | 쓰리엠 이노베이티브 프로퍼티즈 컴파니 | 강성의 뒤틀린 다이비닐 가교결합제를 갖는 설포닐-함유 중합체 재료 |
US10472467B2 (en) * | 2016-09-20 | 2019-11-12 | Dow Global Technologies Llc | Polymers having intrinsic microporosity including sub-units with troger's base and spirobisindane moieties |
WO2018148554A1 (en) * | 2017-02-10 | 2018-08-16 | The Regents Of The University Of California | Inhibition of respiratory complex iii by ligands that interact with a regulatory switch |
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GB0030037D0 (en) * | 2000-12-08 | 2001-01-24 | Karobio Ab | Novel estrogen receptor ligands and methods III |
CA2445922A1 (en) * | 2001-05-10 | 2002-11-21 | Merck & Co., Inc. | Estrogen receptor modulators |
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2003
- 2003-04-17 CN CNA038254476A patent/CN1703393A/zh active Pending
- 2003-04-17 BR BR0315009-7A patent/BR0315009A/pt not_active IP Right Cessation
- 2003-04-17 JP JP2004541201A patent/JPWO2004031125A1/ja not_active Withdrawn
- 2003-04-17 US US10/529,601 patent/US20050256308A1/en not_active Abandoned
- 2003-04-17 EP EP03717627A patent/EP1559707A4/en not_active Withdrawn
- 2003-04-17 CA CA002500869A patent/CA2500869A1/en not_active Abandoned
- 2003-04-17 AU AU2003227412A patent/AU2003227412A1/en not_active Abandoned
- 2003-04-17 RU RU2005113238/04A patent/RU2005113238A/ru not_active Application Discontinuation
- 2003-04-17 MX MXPA05003446A patent/MXPA05003446A/es unknown
- 2003-04-17 KR KR1020057005626A patent/KR20050071534A/ko not_active Application Discontinuation
- 2003-04-17 WO PCT/JP2003/004889 patent/WO2004031125A1/ja not_active Application Discontinuation
- 2003-04-17 PL PL03376472A patent/PL376472A1/xx not_active Application Discontinuation
Non-Patent Citations (3)
Title |
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CARLSON HEATHER A. ET AL.: "Developing a dynamic pharmacophore model for HIV-1 integrase", JOURNAL OF MEDICINAL CHEMISTRY, vol. 43, no. 11, 2000, pages 2100 - 2114, XP000999138 * |
COLLINS DAVID J. ET AL.: "The structure and function of estrogens. I. Synthesis of 4b-methyl-trans-4b,5,6,10b,11,12-hexahydrochrysene-2,8-diol", AUSTRALIAN JOURNAL OF CHEMISTRY, vol. 32, no. 5, 1979, pages 1093 - 1106, XP002971304 * |
See also references of EP1559707A4 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016029101A (ja) * | 2009-06-16 | 2016-03-03 | アンドルシェルシュ・インコーポレイテッド | 性ステロイド前駆体と選択的エストロゲン受容体モジュレーターとの組み合わせによるホットフラッシュ、血管運動症状及び寝汗の治療 |
US10342805B2 (en) | 2009-06-16 | 2019-07-09 | Endorecherche, Inc. | Treatment of Alzheimer's disease, loss of cognition, memory loss and dementia with sex steroid precursors in combination with selective estrogen receptor modulators |
US11452731B2 (en) | 2009-06-16 | 2022-09-27 | Endorecherche, Inc. | Method of treating and preventing loss of cognition |
Also Published As
Publication number | Publication date |
---|---|
KR20050071534A (ko) | 2005-07-07 |
JPWO2004031125A1 (ja) | 2006-02-09 |
MXPA05003446A (es) | 2005-07-05 |
RU2005113238A (ru) | 2006-01-20 |
CA2500869A1 (en) | 2004-04-15 |
EP1559707A1 (en) | 2005-08-03 |
AU2003227412A1 (en) | 2004-04-23 |
US20050256308A1 (en) | 2005-11-17 |
EP1559707A4 (en) | 2006-08-02 |
BR0315009A (pt) | 2005-08-09 |
PL376472A1 (en) | 2005-12-27 |
CN1703393A (zh) | 2005-11-30 |
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