GB2279006A - Treatment of amyotrophic lateral sclerosis - Google Patents
Treatment of amyotrophic lateral sclerosis Download PDFInfo
- Publication number
- GB2279006A GB2279006A GB9311423A GB9311423A GB2279006A GB 2279006 A GB2279006 A GB 2279006A GB 9311423 A GB9311423 A GB 9311423A GB 9311423 A GB9311423 A GB 9311423A GB 2279006 A GB2279006 A GB 2279006A
- Authority
- GB
- United Kingdom
- Prior art keywords
- alkyl
- represent
- independently represent
- lateral sclerosis
- amyotrophic lateral
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/435—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/40—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
Abstract
Macrolide compounds of the formula:- <IMAGE> wherein each vicinal pair of substituents [R<1> and R<2>], [R<3> and R<4>], [R<5> and R<6>] independently a) represent two vicinal hydrogen atoms, or b) form a second bond between the vincinal carbon atoms to which they are attached; in addition to its significance above, R<2> may represent an alkyl group; R<7> represent H, OH, protected hydroxy or O-alkyl, or in conjunction with R<1> it may represent =O; R<8> and R<9> independently represent H or OH; R<10> represents H, alkyl, alkyl substituted by one or more hydroxyl groups, alkenyl, alkenyl substituted by one or more hydroxyl groups, or alkyl substituted by =O; X represents O, (H,OH), (H,H), or -CH2O-; Y represents O, (H,OH), (H,H), N-NR<11>R<12> or N-OR<13>; R<13>, R<14>, R<15>, R<16>, R<17>, R<18>, R<19>, R<22> and R<23> independently represent H or alkyl; R<20> and R<21> independently represent O, or they may independently represent (R<20>a,H) and (R<21>a,H) respectively; R<20>a and R<21>a independently represent OH, O-alkyl or OCH2OCH2CH2OCH3 or R<21>a is protected hydroxy;
Description
NEW USE
This invention relates to a new use of macrolide compounds.
In more detail, this invention relates to a new use of macrolide compounds for preventing or treating amyotrophic lateral sclerosis.
Accordingly, this invention provides a new use of the macrolide compounds for preventing or treating amyotrophic lateral sclerosis.
The macrolide compounds used in this invention are known and disclosed, for example, in European Patent
Publication No. 0184162 and International Publication No.
wo 89/05304.
These known macrolide compounds include the fermentation products, such as FR-900506, FR-900520,
FR-900523 and FR-900525 which were isolated from microorganisms belonging to genus Streptomvces, such as Streptomvces tsukubaensis No. 9993 (FERM BP-927) or Streptomyces hYqroscoPicus subsp. vakushimaensis No. 7238 (FERM BP-928), and their related compounds prepared from these fermentation products.
These macrolide compounds were indicated inter alia for use in the treatment of rejection to transplantation, autoimmune diseases and infectious diseases caused, for example, by Asperqillus, Fusarium, Trichophvton, and the like.
The inventors of this invention have surprisingly found that the macrolide compounds mentioned hereinbelow are active against amyotrophic lateral sclerosis.
The macrolide compounds used in this invention can be represented by the following general formula (I).
wherein each vicinal pair of substituents [R1 and R2], [R3 and R4], [R5 and R6] independently a) represent two vicinal hydrogen atoms, or b) form a second bond between the vicinal carbon atoms to which they are attached;
in addition to its significance above, R2 may represent an alkyl group;
R7 represents H, OH, protected hydroxy or O-alkyl, or in conjunction with R1 it may represent =0; R8 and R9 independently represent H or OH;
R10 represents H, alkyl, alkyl substituted by one or more hydroxyl groups, alkenyl, alkenyl substituted by one or more hydroxyl groups, or alkyl substituted by =O;
X represents 0, (H,OH), (H,H) or -CH2O-;
Y represents 0, (H,OH), (H,H), N-NR11R12 or N-OR13; R11 and R12 independently represent H, alkyl, aryl or tosyl;;
R13, R14, R15, R16, R17, R18 R19, R22 and R23 independently represent H or alkyl;
R20 and R21 independently represent 0, or they may independently represent (R20a,H) and (R21a,H) respectively;
R20a and R21a independently represent OH, O-alkyl or
OCH2OCH2CH2OCH3 or R21a is protected hydroxy;
in addition, R20a and R21a may together represent an oxygen atom in an epoxide ring;
n is 1, 2 or 3;;
in addition to their significances above, Y, R10 and
R23, together with the carbon atoms to which they are attached, may represent a 5- or 6- membered N-, S- or O- containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl, hydroxy, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and -CH2Se(C6H5).
The specific examples of the definitions of compound (I) and the preferred working modes of the invention are described in detail below.
The term " lower " as used in this specification means, unless otherwise indicated, any number of carbon atoms between 1 and 6, inclusive.
Suitable " alkyl " means straight or branched saturated aliphatic hydrocarbon residue and may include lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl, and the like.
Suitable " alkenyl " means straight or branched unsaturated aliphatic hydrocarbon residue having one double bond and may include lower alkenyl such as vinyl, propenyl, butenyl, methylpropenyl, pentenyl, hexenyl, and the like.
Suitable " aryl " may include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, and the like.
Suitable examples of the protective group in the " protected hydroxyl group " may include: 1-(lower alkylthio)(lower)alkyl groups such as lower alkylthiomethyl groups (e.g. methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc.), more desirably C1-C4 alkylthiomethyl groups, and most desirably methylthiomethyl; tri-substituted silyl groups such as tri(lower)alkylsilyl groups (e.g. trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyl-dimethylsilyl, tri-tert-butylsilyl, etc.); lower alkyl-diarylsilyl groups (e.g. methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenylsilyl, etc.), more desirably tri(C1-C4)alkylsilyl and C1-C4 alkyldiphenylsilyl groups and most desirably tert-butyldimethylsilyl and tert-butyldiphenylsilyl; and acyl groups such as aliphatic acyl groups, aromatic acyl groups and aliphatic acyl groups substituted by aromatic groups, which are derived from carboxylic acids, sulfonic acids or carbamic acids.
The aliphatic acyl group may includes lower alkanoyl groups which may optionally have one or more suitable substituents such as carboxy (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxyhexanoyl, etc.), cyclo(lower)alkoxy (lower)alkanoyl groups which may optionally have one or more appropriate substituents such as lower alkyl (e.g.
cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxypentanoyl, menthyloxyhexanoyl, etc.), camphorsulfonyl, lower alkylcarbamoyl groups having one or more suitable substituents such as carboxy or protected carboxy, for example carboxy(lower)alkylcarbamoyl groups( e.g.
carboxymethylcarbamoyl, carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypentylcarbamoyl, carboxyhexylcarbamoyl, etc.), protected carboxy(lower)alkylcarbamoyl groups such as tri(lower)alkylsilyl(lower)alkoxycarbonyl(lower)alkylcarbamoyl groups(e.g. trimethylsilylmethoxycarbonylethylcarbamoyl, trimethylsilylethoxycarbonylpropyl carbamoyl, triethylsilylethoxycarbonylpropylcarbamoyl, tert-butyldimethylsilylethoxycarbonylpropylcarbamoyl, trimethylsilylpropoxycarbonylbutylcarbamoyl, etc.) and so on.
The aromatic acyl group may include aroyl groups which may optionally have one or more suitable substituents such as nitro (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl, etc), arenesulfonyl groups which may optionally have one or more suitable substituent(s) such as halogen (e.g.
benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl, etc.), and so on.
The aromatic group-substituted aliphatic acyl group may include ar(lower)alkanoyl groups which may optionally have one or more suitable substituent(s) such as lower alkoxy and trihalo(lower)alkyl (e.g. phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2 -methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl2-propoxy-2-phenylacetyl, etc.), and so on.
Among the above-mentioned acyl groups, the more desirable acyl groups are C1-C4 alkanoyl groups which may optionally be substituted by carboxy, cyclo(Cs-C6)alkyloxy- (Cl-C4)alkanoyl groups having two (Cl-C4)alkyl groups in the cycloalkyl moiety, camphorsulfonyl, carboxy(C1-Cq)alkyl- carbamoyl groups, tri(C1-C4)alkylsilyl(Cl-C4)alkoxycarbonyl- (C1-C4)alkylcarbamoyl groups, benzoyl which may have one or two nitro groups, halogen-substituted benzenesulfonyl groups, phenyl(C1-C4)alkanoyl groups having C1-C4 alkoxy and trihalo(C1-C4)alkyl groups.Of these groups, the most desirable are acetyl, carboxypropionyl, menthyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and 2-trifluoromethyl-2methoxy-2-phenylacetyl.
Suitable " 5- or 6-membered N-, S- or O-containing heterocyclic ring " may include pyrrolyl, tetrahydrofuryl, and the like.
Preferred embodiments of the Symbols R1 to R10, R14 to
R23, X, Y and n are as follows.
R1 and R2 are each hydrogen or combined to form a second bond;
R3 and R4 are combined to form a second bond;
R5 and R6 are combined to form a second bond;
R7 is hydrogen, hydroxy, O-lower alkyl such as methoxy or protected hydroxy;
R8 is hydrogen or hydroxy;
R9 is hydroxy;
R10 is methyl, ethyl, propyl, allyl or 2-oxopropyl;
R14, R15, R16, R17, R18 and R19 are each methyl;
R20 is oxo or [R20a,H], wherein R20a is hydroxy or methoxy;
R21 is [R21a,H], wherein R21a is hydroxy or protected hydroxy;
R23 is hydrogen;
X is oxo, (H,OH) or (H,H);
Y is oxo; and
n is 1 or 2.
The pharmaceutically acceptable salt of the compound (I) is a nontoxic salt, which may be the corresponding salt with an inorganic or organic base such as alkali metal salts (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g. calcium salt, magnesium salt, etc.), ammonium salt and amine salts (e.g. triethylamine salt,
N-benzyl-N-methylamine salt, etc.) and so on.
Regarding the macrolide compounds (I), there may exist one or more conformers, or one or more stereoisomeric pairs such as optical and geometrical isomers due to the asymmetric carbon(s) or the double bond(s). Such conformers and isomers also fall within the scope of the invention.
Particularly, the most interesting compound is
FR-900506 of the following formula.
described as FK506) The macrolide compounds (I) of the present invention can be administered in a pure or impure form and in a single compound or a mixture thereof, preferably, in a pharmaceutical vehicle or carrier.
The pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the macrolide compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, intravenous, intramuscular, or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable, carriers for ointment, cream, plaster, tablets, pellets, capsules, suppositories, solutions (saline, for example), emulsion, suspensions (olive oil, for example), and any other form suitable for use.The carriers which can be used are water, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active compound is included in the pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the diseases.
Mammals which may be treated by the present invention include livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc.. and humans, preferably humans.
For applying this composition to a human, it is preferable to apply it by external (topical), oral, parenteral, enteral, intravenous, or intramuscular administration.
While the dosage of therapeutically effective amount of the macrolide compounds varies from and. also depends upon the age and condition of each individual patient to be treated, in case of the systemic administration, a daily dose of about 0.01-1000 mg, preferably 0.1-500 mg and more preferably 0.5-100 mg. of the active ingredient is generally given for treating the diseases, and an average single dose of about 0.2-0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg is generally administered. Daily doses for chronic administration in humans will be in the range of about 0.3 mg/kg/day.
And further, it is considered that the compounds described in the European Patent Publication Nos. 0349049, 0349061, 0358508, 0364031, 0364032, 0378317, 0378320, 037321, 0388153, 0396399, 0396400, 0399579, 0403242, 0356399, 0402931, 0353678; British Patent Publication No.
2225576; International Patent Application Nos.
PCT/GB90/01262 and PCT/JP91/00314; Japanese Patent
Application No. 3-53588 (1991), and so on, are also useful for the diseases shown in the present specification.
The following examples are given for the purpose of illustrating the present invention.
Example 1
FK 506 1g Hydroxypropyl methylcellulose 2910 (TC-SR) 1 g
Lactose 2g Croscarmellose sodium (Ac-Di-Sol) 1 g
FK506 (1 g) was dissolved in ethanol (10 ml), and thereto was added hydroxypropyl methylcellulose 2910 (TC-SR) (1 g) to prepare a suspension. To this suspension was added dichloromethane (5 ml) to prepare a homogeneous solution.
Lactose (2 g) and croscarmellose sodium (Trade Mark:
Ac-Di-Sol, maker: Asahi Chemical Industry) were homogeneously suspended to this solution, and then the organic solvent was removed by evaporation. The residual product was dried under reduced pressure for 10 hours by vacuum dryer, milled for 2 minutes by coffee mill and then passed through a sieve (32 mesh) to give the solid dispersion composition of FK506 (5 g) (hereinafter, described as SDF). This composition was capsulated by a conventional manner to provide capsules containing 1 mg or 5 mg of FK506 per each capsule.
ExamPle 2
FK 506 lOmg HCO-60 400mg Ethanol to lml
The solution comprising the ingredients stated above is prepared by dissolving the FK 506 and HCO-60 in ethanol by a conventional manner. It can be administered via i.v.
infusion by diluting with a proper volume of physiological saline.
Example 3
FK 506 2mg
Polysorbate 50mg Propylene glycol to lml
The above solution is prepared in a similar manner of the Example 2.
Claims (8)
1. A use of macrolide compounds of the formula:
wherein each vicinal pair of substituents [R1 and R2],
[R3 and R4], [R5 and R6] independently
a) represent two vicinal hydrogen atoms, or
b) form a second bond between the vicinal
carbon atoms to which they are attached;
in addition to its significance above, R2 may
represent an alkyl group;
R7 represents H, OH, protected hydroxy or
O-alkyl, or in conjunction with R1 it may
represent =0; R8 and R9 independently represent H or OH;
R10 represents H, alkyl, alkyl substituted by
one or more hydroxyl groups, alkenyl,
alkenyl substituted by one or more hydroxyl
groups, or alkyl substituted by =O;
X represents 0, (H,OH), (H,H) or -CH2O-;
Y represents 0, (H,OH), (H,H), N-NR11R12 or
N-OR13;; R11 and R12 independently represent H, alkyl,
aryl or tosyl;
R13, R14, R15, R16, R17, R187 R19, R22 and R23
independently represent H or alkyl;
R20 and R21 independently represent 0, or they
may independently represent (R20a,H) and
(R21a,H) respectively;R20a and R21a
independently represent OH, O-alkyl or
OCH2OCH2CH2OCH3 or R21a is protected
hydroxy;
in addition,'R20a and R21a may together
represent an oxygen atom in an epoxide ring;
n is 1, 2 or 3;
in addition to their significances above, Y, R10
and R237 together with the carbon atoms to which
they are attached, may represent a 5- or 6
membered N-, S- or 0- containing heterocyclic
ring, which may be saturated or unsaturated, and
which may be substituted by one or more groups
selected from alkyl, hydroxy, alkyl substituted
by one or more hydroxyl groups, O-alkyl, benzyl
and -CH2Se(C6Hs);
or a pharmaceutically acceptable salt thereof, for
preventing or treating amyotrophic lateral sclerosis.
2. A use of the macrolide compounds (I) defined in Claim 1
as a prophylactic or therapeutic agent for amyotrophic
lateral sclerosis.
3. A prophylactic or therapeutic agent for amyotrophic
lateral sclerosis, which comprises the macrolide
compounds (I) defined in Claim 1.
4. A method for preventing or treating amyotrophic lateral
sclerosis, which comprises administering the macrolide
compounds (I) defined in claim 1 to mammals.
5. A use of the macrolide compounds (I) defined in claim 1
for manufacturing a medicament for preventing or treating
amyotrophic lateral sclerosis.
6. A pharmaceutical composition for treating or preventing
amyotrophic lateral sclerosis, which comprises the
macrolide compounds (I) defined in Claim 1 in admixture
with a carrier or excipient.
7. A process for preparing the pharmaceutical composition of
Claim 6, which is characterized by admixing the macrolide
compounds (I) with a carrier or excipient.
8. The macrolide compound used in either one of Claims 1 to
7 is Fur506.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9311423A GB2279006A (en) | 1993-06-03 | 1993-06-03 | Treatment of amyotrophic lateral sclerosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9311423A GB2279006A (en) | 1993-06-03 | 1993-06-03 | Treatment of amyotrophic lateral sclerosis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9311423D0 GB9311423D0 (en) | 1993-07-21 |
| GB2279006A true GB2279006A (en) | 1994-12-21 |
Family
ID=10736541
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9311423A Withdrawn GB2279006A (en) | 1993-06-03 | 1993-06-03 | Treatment of amyotrophic lateral sclerosis |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2279006A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996040140A1 (en) * | 1995-06-07 | 1996-12-19 | Guilford Pharmaceuticals Inc. | Inhibitors of rotamase enzyme activity |
| US5898029A (en) * | 1994-04-12 | 1999-04-27 | The John Hopkins University | Direct influences on nerve growth of agents that interact with immunophilins in combination with neurotrophic factors |
| EP1281400A2 (en) * | 1995-07-14 | 2003-02-05 | Novartis AG | Pharmaceutical compositions containing ascomycin derivatives |
| WO2014188197A1 (en) * | 2013-05-24 | 2014-11-27 | Chronos Therapeutics Limited | Tacrolimus for use in treating diseases characterised by protein aggregate deposition in neuronal cells |
| WO2017118857A1 (en) * | 2016-01-08 | 2017-07-13 | Chronos Therapeutics Limited | Tacrolimus for treating tdp-43 proteinopathy |
| US20180085356A1 (en) * | 2013-05-24 | 2018-03-29 | Chronos Therapeutics Limited | Method of treating disease characterised by protein aggregate deposition in neuronal cells |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0184162A2 (en) * | 1984-12-03 | 1986-06-11 | Fujisawa Pharmaceutical Co., Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
| WO1989005304A1 (en) * | 1987-12-09 | 1989-06-15 | Fisons Plc | Macrocyclic compounds |
-
1993
- 1993-06-03 GB GB9311423A patent/GB2279006A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0184162A2 (en) * | 1984-12-03 | 1986-06-11 | Fujisawa Pharmaceutical Co., Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
| WO1989005304A1 (en) * | 1987-12-09 | 1989-06-15 | Fisons Plc | Macrocyclic compounds |
Cited By (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5898029A (en) * | 1994-04-12 | 1999-04-27 | The John Hopkins University | Direct influences on nerve growth of agents that interact with immunophilins in combination with neurotrophic factors |
| US6080753A (en) * | 1994-04-12 | 2000-06-27 | Johns Hopkins University School Of Medicine | Stimulating nerve growth with immunophilins |
| ES2194596A1 (en) * | 1995-06-07 | 2003-11-16 | Guilford Pharm Inc | Inhibitors of rotamase enzyme activity |
| GB2305605A (en) * | 1995-06-07 | 1997-04-16 | Guilford Pharm Inc | Inhibitors of rotamase enzyme activity |
| DE19680255T1 (en) * | 1995-06-07 | 1997-06-05 | Guilford Pharm Inc | Rotamase enzyme activity inhibitors |
| ES2138518A1 (en) * | 1995-06-07 | 2000-01-01 | Guilford Pharm Inc | Inhibitors of rotamase enzyme activity |
| GB2305605B (en) * | 1995-06-07 | 2000-01-12 | Guilford Pharm Inc | Pipecolic acid derivatives for the treatment of neurological disorders |
| US6022878A (en) * | 1995-06-07 | 2000-02-08 | Gpi Nil Holdings, Inc. | Inhibitors of rotamase enzyme activity |
| ES2166740A1 (en) * | 1995-06-07 | 2002-04-16 | Guilford Pharm Inc | Inhibitors of rotamase enzyme activity |
| US6500843B2 (en) | 1995-06-07 | 2002-12-31 | Gpi Nil Holdings, Inc. | Inhibitors of rotamase enzyme activity |
| WO1996040140A1 (en) * | 1995-06-07 | 1996-12-19 | Guilford Pharmaceuticals Inc. | Inhibitors of rotamase enzyme activity |
| EP1281400A2 (en) * | 1995-07-14 | 2003-02-05 | Novartis AG | Pharmaceutical compositions containing ascomycin derivatives |
| EP1281400A3 (en) * | 1995-07-14 | 2003-11-05 | Novartis AG | Pharmaceutical compositions containing ascomycin derivatives |
| US6599535B2 (en) | 1995-07-14 | 2003-07-29 | Novartis Ag | Pharmaceutical compositions |
| US6956043B2 (en) | 1995-07-14 | 2005-10-18 | Novartis Ag | Pharmaceutical compositions comprising 33-epi-chloro-33-desoxy-ascomycin solid dispersions |
| WO2014188197A1 (en) * | 2013-05-24 | 2014-11-27 | Chronos Therapeutics Limited | Tacrolimus for use in treating diseases characterised by protein aggregate deposition in neuronal cells |
| JP2016528171A (en) * | 2013-05-24 | 2016-09-15 | クロノス セラピューティクス リミテッドＣｈｒｏｎｏｓ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｉｍｉｔｅｄ | Tacrolimus for use in the treatment of diseases characterized by the deposition of protein aggregates in neurons |
| US20160296500A1 (en) * | 2013-05-24 | 2016-10-13 | Chronos Therapeutics Limited | Tacrolimus for use in treating diseases characterized by protein aggregate deposition in neuronal cells |
| US20180085356A1 (en) * | 2013-05-24 | 2018-03-29 | Chronos Therapeutics Limited | Method of treating disease characterised by protein aggregate deposition in neuronal cells |
| WO2017118857A1 (en) * | 2016-01-08 | 2017-07-13 | Chronos Therapeutics Limited | Tacrolimus for treating tdp-43 proteinopathy |
| CN108601772A (en) * | 2016-01-08 | 2018-09-28 | 克罗诺斯治疗有限公司 | Tacrolimus for treating TDP-43 protein sickness |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9311423D0 (en) | 1993-07-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |