Inventors: Kakihana; Mitsuru (Kobe, JP); Kosaka; Takuo (Nerima-ku, JP); Nagaoka; Akinobu (Kawanishi, JP); Goto; Giichi (Toyono-gun, JP) Assignee: Takeda Chemical Industries, Ltd. (Osaka, JP) Appl. No.: 646354 Filed: May 10, 1996

Primary Examiner: Criares; Theodore J. Attorney, Agent or Firm: Wenderoth, Lind & Ponack, L.L.P. United States 5,965,568 October 12, 1999

Parent Case Text
This application is a 371 of PCT/JP 96/00265 filed Feb. 8, 1996.

Claims
We claim:

1. A method of preventing or treating Down's syndrome, which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I): ##STR7## wherein ring A is an optionally substituted benzene ring, R represents OR.sup.1, ##STR8## or SR.sup.1, wherein R.sup.1, R.sup.2 and R.sup.3 are the same or differentand each is selected from a hydrogen atom, an optionally substituted hydrocarbon group or R.sup.2 and R.sup.3, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen-containing heterocyclic group, and Y is an optionally substituted alkyl group, or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the ring A is a benzene ring which may have 1 to 3 substituents selected from halogen, R is OR.sup.1 wherein R.sup.1 is alkyl, and Y is ethyl.

3. The method according to claim 2, wherein the ring A is a benzene ring, and R.sup.1 is ethyl.

4. The method according to claim 1, wherein the compound is administered in the form of a composition including a pharmaceutically acceptable excipient, carrier or diluent.

Description
BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a composition, particularly a pharmaceutical composition, for inhibiting production or secretion of an amyloid .beta. protein. The composition is effective in treating degenerative brain disorders such as senile dementia, Alzheimer's disease, Down's syndrome, etc., amyloid angiopathy, brain disorders caused by amyloid .beta. protein in cerebrovascular diseases, etc.

2. Description of Related Art

Alzheimer's disease is a neurodegenerative disease characterized by senile plaque and neurofibrillar tangles as well as degeneration and loss of neurons. The senile plaques, which are most characteristic of the disease, are deposits composed of amyloid .beta. protein (hereinafter sometimes abbreviated as A.beta.) derived from .beta.-amyloid precursor protein (hereinafter sometimes abbreviated as .beta.APP) as a major component (Biochem. Biophys. Res. Commun., 122, 1131 (1984)), apolipoprotein E (Brain Res., 541, 163 (1991)) and heparan sulfate proteoglycan (Am. J. Pathol., 133, 456 (1988)), etc.

A.beta. of 40 or 42 amino acids exhibits toxicity to neurons (Science, 250, 279 (1990)), and induces neurofibrillar changes (Proc. Natl. Acad. Sci., 90, 7789 (1993)). In patients with familial Alzheimer's disease, mutations on the .beta.APP gene are observed (Lancet, 337, 978 (1991); Nature, 349, 704 (1991); Science, 254, 97 (1991); Nature, 354, 844 (1991)). Cells containing such mutated gene produce and secrete an increased amount of A.beta. (Nature, 360, 672 (1992); Science, 259, 514 (1993); Science, 264, 1336 (1994)).

Patients with Down's syndrome showing cerebral changes pathologically similar to those of Alzheimer's disease (Proc. Natl. Acad. Sci., 82, 4245 (1985)) have trisomy 21 (i.e., three chromosome 21s containing the .beta.APP gene) and promoted expression of the .beta.APP gene and .beta.APP protein in the brain (Science, 235, 880 (1987); N. Eng. J. Med., 320, 1446 (1989)).

Based on these findings, the participation of the abnormal production or secretion of A.beta. in the onset of Alzheimer's disease is considered to be highly important.

It is believed that .beta.APP is metabolized with proteases called .alpha.- and .beta.-secretases through two pathways (Science, 248, 492 (1990); Science, 248, 1122 (1990); Science, 255, 726 (1992); Science, 255, 728 (1992); Nature, 357, 500 (1992)). When .beta.APP is metabolized with a-secretase, .beta.APP is cleaved at position 16 of A.beta., A.beta. is not produced, and the N-terminal fragment of .beta.APP is released out of the cells as secreted .beta.APP, which acts as a neurotrophic factor (Neuron, 10, 243-254 (1993)). On the other hand, when .beta.APP is cleaved with .beta.-secretase, a C-terminal fragment of .beta.APP containing A.beta.is produced. However, it is unclear where the C-terminal fragment or A.beta. is produced in the cells and how A.beta. is secreted out of the cells. In addition, although candidate enzymes for .alpha.- and .beta.-secretases have been reported (J. Biol. Chem., 268, 16699 (1993); Biochemistry, 33, 192 (1994)), they have not identified.

It has been reported that some compounds, phorbol esters (Proc. Natl. Acad. Sci., 89, 3055 (1992)) and M1 muscarinic receptor agonist, carbacol (Science, 258, 302 (1992)) increase the secreted .beta.APP and inhibit A.beta. production or secretion in in vitro various cells. However, these compounds are unsatisfactory in terms of efficacy, safety, etc.

SUMMARY OF THE INVENTION

The present inventors have intensively studied to find an inhibitor of A.beta. production or secretion. As a result, it has been found that vinpocetine (CALAN.TM.) or a derivative thereof has inhibitory activity against A.beta. production or secretion.

Vinpocetine or its derivative is a known compound disclosed in JP-B 51-32640 (U.S. Pat. No. 4,035,370) and JP-B 2-27352 (U.S. Pat. No. 4,400,514). However, these publications only disclose cerebro-vasodilative, systemic-vasodilative and hypotensive activities of the compound, and fails to teach or suggest inhibitory activity against A.beta. production or secretion.

The present invention provides a pharmaceutical composition for inhibiting production or secretion of amyloid .beta. protein, particularly for preventing or treating Alzheimer's disease, which comprises a compound of the formula (I): ##STR3## wherein ring A is an optionally substituted benzene ring, R represents OR.sup.1, ##STR4## or SR.sup.1, wherein R.sup.1, R.sup.2 and R.sup.3 are the same or different and each is selected from a hydrogen atom, an optionally substituted hydrocarbon group or R.sup.2 and R.sup.3, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen-containing heterocyclic group, and Y is an optionally substituted alkyl group, or a pharmaceutically acceptable salt thereof, if necessary, with a pharmaceutically acceptable excipient, carrier or diluent.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT(S)

"Hydrocarbon group" of the term "optionally substituted hydrocarbon group" used in this specification include, among others, aliphatic hydrocarbon groups, monocyclic saturated hydrocarbon groups and aromatic hydrocarbon groups. The carbon number of the hydrocarbon group is preferably 1 to 16. An alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group and an aryl group are exemplified.

"Alkyl group" is preferably a lower alkyl group, for example, C.sub.1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl are used.

"Alkenyl group" is preferably a lower alkenyl group, for example, C.sub.2-6 alkenyl groups such as vinyl, 1-propenyl, allyl, isopropenyl, butenyl and isobutenyl are used.

"Alkynyl group" is preferably a lower alkynyl group, for example, C.sub.2-6 alkynyl groups such as ethynyl and 1-propynyl are used.

"Cycloalkyl group" is preferably a lower cycloalkyl group, for example, C.sub.3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are used.

"Aryl group" is preferably C.sub.6-14 aryl groups such as phenyl, xylyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-indenyl and 2-anthlyl. Among others, a phenyl group, for example, is used.

Examples of the substituents, which "hydrocarbon group" of "optionally substituted hydrocarbon group" may optionally have, include halogen atoms, (e.g. fluorine, chlorine, bromine and iodine), a nitro group, a cyano group, a hydroxyl group, optionally halogenated C.sub.1-6 alkyl groups (e.g. methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trif luoropentyl, hexyl and 6,6,6-trifluorohexyl), lower alkoxy groups (e.g. C.sub.1-6 alkoxy groups such as methoxy, ethoxy, propoxy, isopopoxy, butoxy, isobutoxy, pentyloxy and hexyloxy), an amino group, mono-lower alkylamino groups (e.g. mono-C.sub.1-6 alkylamino groups such as methylamino and ethylamino), di-lower alkylamino groups (e.g. di-C.sub.1-6 alkylamino groups such as dimethylamino and diethylamino), a carboxyl group, lower alkylcarbonyl groups (e.g. C.sub.1-6 alkyl-carbonyl groups such as acetyl and propionyl), lower alkoxycarbonyl groups (e.g. C.sub.1-6 alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl), a carbamoyl group, mono-lower-alkylcarbamoyl groups (e.g. mono-C.sub.1-6 alkylcarbamoyl groups such as methylcarbamoyl and ethylcarbamoyl), di-lower alkylcarbamoyl groups (e.g. di-C.sub.1-6 alkylcarbamoyl groups such as dimethylcarbamoyl and diethylcarbamoyl), arylcarbamoyl groups (e.g. C.sub.6-10 arylcarbamoyl groups such as phenylcarbamoyl and naphthylcarbamoyl), aryl groups (e.g. C.sub.6-10 aryl groups such as phenyl and naphthyl) and aryloxy groups (e.g. C.sub.6-10 aryloxy groups such as phenyloxy and naphthyloxy), optionally halogenated lower alkylcarbonylamino groups (e.g. optionally halogenated C.sub.1-6 alkyl-carbonylamino groups such as acetylamino, trifluoroacetylamino). "Hydrocarbon group" of "optionally substituted hydrocarbon group" may optionally have 1 to 5, preferably 1 to 3, of these substituents. When the number of the substituents is two or more, they may be the same one or different from one another.

Examples of "nitrogen-containing heterocyclic group" formed by R.sup.2, R.sup.3 and the adjacent nitrogen atom include 4- to 8-membered heterocyclic groups each of which contains at least one nitrogen atom and may contain 1 to 3, preferably 1 to 2, oxygen atoms, sulfur atoms, etc. in addition to carbon atoms as the ring-constituting atoms, and their benzo-condensed groups.

Specific examples of the nitrogen-containing heterocyclic groups include aromatic heterocyclic groups such as 1-pyrrolyl, 1-imidazolyl, 1-indolyl, 1-pyrazolyl, 2-isoindolyl, 1-indazolyl, etc.; cyclic amino groups such as morpholino, piperidino, 1-piperazinyl optionally having a substituent on the nitrogen atom at the 4-position, 1-pyrrolidinyl, 1-pyrazolidinyl, 1-azepinyl, etc.; or their benzo-condensed groups (e.g. 1-indolinyl, 2-isoindolinyl, 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 3-benzazepin-3-yl); lactam or imido groups such as phthalimido, succinimido, 2-pyrrolidon-1-yl, 2-pyridon-1-yl, 2-quinolon-1-yl, etc.

"Nitrogen-containing heterocyclic group" formed by R.sup.2, R.sup.3 and the adjacent nitrogen atom may have the same substituents as those described above for "optionally substituted hydrocarbon group". The benzo-condensed group may have one or more substituents at any possible position on the benzene ring. The substituents are selected from halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.), lower alkylendioxy groups (e.g. C.sub.1-3 alkylenedioxy groups such as methylenedioxy, ethylenedioxy, etc.), a nitro group, a cyano group, optionally halogenated lower alkyl groups (e.g. optionally halogenated C.sub.1-6 alkyl groups such as chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and 6,6,6-trifluorohexyl), optionally halogenated lower alkoxy groups (e.g. optionally halogenated C.sub.1-6 alkoxy groups such as chloromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, ethoxy, 2-bromoethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, propoxy, 3,3,3-trifluoropropoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 5,5,5-trifluoropentyloxy, hexyloxy and 6,6,6-trifluorohexyloxy), optionally halogenated lower alkylthio groups (e.g. optionally halogenated C.sub.1-6 alkylthio groups such as chloromethylthio, difluoromethylthio, trichloromethylthio, trifluoromethylthio, ethylthio, 2-bromoethylthio, 2,2,2-trifluoroethylthio, pentafluoroethylthio, propylthio, 3,3,3-trifluoropropylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, 5,5,5-trifluoropentylthio, hexylthio and 6,6,6-trifluorohexylthio), a hydroxyl group, an amino group, mono-lower alkylamino groups (e.g. mono-C.sub.1-6 alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), di-lower alkylamino groups (e.g., di-C.sub.1-6 alkylamino groups such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), a carboxyl group, lower alkoxycarbonyl groups (e.g., C.sub.1-6 alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.) and a carbamoyl group.

"Alkyl group" of the term "optionally substituted alkyl group" used in this specification includes, for example, C.sub.1-15 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, preferably lower (C.sub.1-6) alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. The alkyl group may optionally have 1 to 3 substituents which, for example, the above-mentioned "hydrocarbon group" may optionally have.

The term "optionally substituted benzene ring" used in this specification means a benzene ring which optionally have, at any possible position, one to three substituents selected from halogen atoms (e.g. fluorine, chlorine, bromine and iodine), optionally substituted hydrocarbon groups, optionally substituted hydroxyl groups (preferably, optionally substituted lower (C.sub.1-6) alkoxy groups such as methoxy, ethoxy, propoxy and isopropoxy), an optionally substituted amino group, amido groups (e.g. C.sub.1-6 acylamino groups such as acetamido), and lower alkylenedioxy groups (e.g. C.sub.1-6 alkylenedioxy groups such as methylenedioxy, ethylenedioxy).

The term "optionally substituted amino group" used in this specification means an amino group which may optionally have, as the substituents, one or two of the above-mentioned "optionally substituted hydrocarbon group" for example. Preferable examples of the substituents, which this "amino group" may optionally have, include an optionally substituted C.sub.1-6 alkyl group and an optionally substituted C.sub.6-10 aryl group. The substituents of the alkyl or aryl group are, for example, the same substituents which above-mentioned "hydrocarbon group" may optionally have.

The term "optionally substituted hydroxyl group" used in this specification means a hydroxyl group which may have, in place of the hydrogen atom of the hydroxyl group, one "optionally substituted hydrocarbon group" mentioned above. preferable examples of "substituted hydroxyl group" include a hydroxyl group substituted with one lower alkyl group. Examples of the "lower alkyl group" include C.sub.1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. The substituents which "lower alkyl group" may optionally have are, for example, the same ones as the above-mentioned "hydrocarbon group" may optionally have.

The "optionally substituted hydrocarbon group" includes the same ones as those mentioned above. When the number of the substituents is two or more, they may be the same one or different from one another.

In the above formulae, ring A is an optionally substituted benzene ring. Preferable examples of ring A include an unsubstituted benzene ring or benzene rings having 1 to 3 substituents selected from halogen atoms (e.g. fluorine and chlorine), C.sub.1-6 alkyl groups (e.g. methyl and ethyl), C.sub.1-6 alkoxy groups (e.g. methoxy and ethoxy) which may have a C.sub.6-10 aryl group, hydroxyl group and mono-C.sub.1-6 alkylamino group, especially preferable one being, for example, a benzene ring substituted with one, for example, C.sub.1-6 alkoxy group (e.g. methoxy).

Among others, ring A is preferably an unsubstituted benzene ring or benzene rings having 1 to 3 halogen atoms (e.g. fluorine and chlorine). More preferably, ring A is a benzene ring.

In the above formulae, R represents OR.sup.1, ##STR5## or SR.sup.1, wherein R.sup.1, R.sup.2 and R.sup.3 are the same or different and each is selected from a hydrogen atom, an optionally substituted hydrocarbon group or R.sup.2 and R.sup.3, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen-containing heterocyclic group.

Preferable examples of "hydrocarbon group" shown by R.sup.1, R.sup.2 and R.sup.3 include alkyl groups (e.g., C.sub.1-6 alkyl groups such as methyl, ethyl, propyl and isopropyl), alkenyl groups (e.g. C.sub.2-6 alkenyl groups such as vinyl), alkynyl groups (e.g. C.sub.2-6 alkynyl groups such as ethynyl), cycloalkyl groups (e.g. C.sub.3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl) and aryl groups (e.g. C.sub.6-14 aryl groups such as phenyl). Among others, alkyl groups (e.g. C.sub.1-6 alkyl groups such as methyl) and cycloalkyl groups (e.g. C.sub.3-6 cycloalkyl groups such as cyclopropyl) are preferably used. The "alkyl group", "alkenyl group", "alkynyl group", "cycloalkyl group", and "aryl group" may optionally have, for example, 1 to 5, preferably 1 to 3 substituents, which the above-mentioned "hydrocarbon group" may optionally have, (preferably halogen atoms such as fluorine).

A preferable example of R is OR.sup.1 wherein R.sup.1 is an alkyl group, more preferably, R.sup.1 is ethyl.

In the above formulae, Y is an optionally substituted alkyl group. Preferable examples of Y are lower (C.sub.1-6) alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl). More preferable examples of Y include ethyl.

Preferable examples of the compound (I) include the compound of the formula (II): ##STR6## wherein X is hydrogen or halogen and R.sup.4 is alkyl, and the preferable compounds may be, if necessary, used with a pharmaceutically acceptable excipient, carrier or diluent.

The halogen represented by X in the formula (II) includes fluorine, chlorine, bromine, and iodine. The alkyl represented by R.sup.4 includes, for example, alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and hexyl. Methyl and ethyl are preferred. In particular, vinpocetine, i.e. the compound of the formula (II) wherein X is hydrogen and R.sup.4 is ethyl, is preferred.

The pharmaceutically acceptable salts of the compound of the formula (I) include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid, salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

The compound of the formula (I) or a pharmaceutically acceptable salt thereof can be prepared by known methods disclosed in, for example, above JP-B 51-32640 (corresponding to D.E. Patent 2,253,750 and U.S. Pat. No. 4,035,370) and above JP-B 2-27352 (corresponding to U.S. Pat. No. 4,400,514).

The compound of the formula (I) or a pharmaceutically acceptable salt thereof can be used by per se known methods as an inhibitor of A.beta. production or secretion, in particular as an agent for preventing or treating Alzheimer's disease. For example, it can be administered orally or parenterally to mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey and man) in various conventional dosage forms, such as tablets, granules, fine granules, capsules, injections, and suppositories.

For example, tablets can be prepared by granulating the medicine per se or a homogeneous mixture or it with an excipient, binder, disintegrator or other appropriate additives by appropriate methods, and then compress-shaping the resulting granules with a lubricant, etc., or by directly compress-shaping the medicine per se or a homogeneous mixture of it with an excipient, binder, disintegrator or other appropriate additives, or by compress-shaping previously-prepared granules or a homogeneous mixture of them with appropriate additives. If necessary, colorants, corrigents, etc., can be added to the composition. In addition, the composition may be coated with an appropriate coating agent.

Injections can be prepared by dissolving, suspending or emulsifying an appropriate amount of the medicine in an appropriate amount of an aqueous solvent such as water for injection, physiological saline, Ringer's solution, etc., or a nonaqueous solvent such as conventional vegetable oils, etc. Alternatively, injections can be prepared by filling an appropriate amount of the medicine into a vial for injection and sealing the vial.

Examples of carriers for oral compositions include materials commonly used in the art, such as starch, mannit, crystalline cellulose, carboxymethylcellulose sodium, etc. Examples of carriers for injections include distilled water, physiological saline, glucose solutions, transfusion solutions, etc. In addition, additives commonly used in the art can appropriately be added.

The dose varies with the subject disease, administration route, symptoms, etc. In general, it is 0.1 mg to 500 mg, preferably 1 mg to 100 mg, more preferably 1 mg to 20 mg, per day for a human adult.

Vinpocetine has been used as a medicament, and it has no toxic problems and can safely be administered.

As described above, the inhibitor of A.beta. secretion or production of the invention is useful for treating or preventing brain disorders in mammals including humans. The subject diseases include, for example, senile dementia, Alzheimer's disease, cerebrovascular dementia, amyloid angiopathy, and Down's syndrome.