CN101505749A - Use of PKC inhibitors in particular indolylmaleimide derivatives in ocular diseases - Google Patents
Use of PKC inhibitors in particular indolylmaleimide derivatives in ocular diseases Download PDFInfo
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- CN101505749A CN101505749A CNA2007800304039A CN200780030403A CN101505749A CN 101505749 A CN101505749 A CN 101505749A CN A2007800304039 A CNA2007800304039 A CN A2007800304039A CN 200780030403 A CN200780030403 A CN 200780030403A CN 101505749 A CN101505749 A CN 101505749A
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Abstract
The present invention pertains to the use of a PKC inhibitor in the treatment of an ocular disorder.
Description
The present invention relates to pkc inhibitor treatment or prevention ophthalmic and disorderly, particularly relate to ophthalmic that inflammation and/or new vessels form and disorderly as the purposes in degeneration of macula (AMD), uveitis, diabetic retinopathy or the diabetic macular edema.
Degeneration of macula is the ophthalmic that is difficult to cure, and it causes irreversible central vision forfeiture.It is the most general reason that causes losing one's sight in the people at 55 years old and bigger age.Along with people's age increase, the chance that ophthalmic and particularly AMD take place for they significantly increases.
Age-related macular degeneration (ARMD) is the common form of degeneration of macula.It is also referred to as age related maculopathy (ARM), old property degeneration of macula and age-related macular degeneration.
Uveitis is the disease of ophthalmia disease, particularly uveal disease.This comprises iris, corpus ciliare and choroidal inflammation.According to the position of inflammation, it also can be described to anterior uveitis, middle uveitis (intermediate uveitis), back uveitis or panuveitis.
Although there is multiple treatment option to treat or prevent these diseases and disorder, disease continues development, and still needs effective and safe treatment.
The invention provides pkc inhibitor, particularly Indolylmaleimide derivatives in prevention or treatment or delay to relate to inflammation and/or ophthalmic that new vessels forms and the purposes in the disorder, wherein said Indolylmaleimide derivatives is formula (I) compound or pharmaceutically acceptable salt thereof
Wherein
R
aBe H; C
1-4Alkyl; Or by OH, NH
2, NHC
1-4Alkyl or N (two-C
1-4Alkyl)
2The C that replaces
1-4Alkyl; And
R is formula (a) or (b) group
Wherein
R
1And R
11Each is heterocyclic group naturally; NR
4R
5, R wherein
4And R
5Form heterocyclic group with their bonded nitrogen-atoms;
R
2, R
3, R
12And R
13Be H, halogen, C independently of one another
1-4Alkyl, CF
3, OH, SH,
NH
2, C
1-4Alkoxyl, C
1-4Alkylthio group, NHC
1-4Alkyl, N (two-C
1-4Alkyl)
2Or CN;
And
Ring A is optional substituted.
In formula (I), arbitrarily alkyl or moieties (in alkoxyl for example) can be linear or ramose.Halogen can be F, Cl, Br or I, preferred F or Cl.Aryl can be a phenyl or naphthyl arbitrarily, preferred phenyl.
As R
1Or R
11Or by NR
4R
5Formed heterocyclic group means hetero atom and optional substituted 3 to 8 yuan, preferred 5 to 8 yuan of saturated, the unsaturated or heteroaromatics that comprise 1 or 2 hetero atom, are preferably selected from N, O and S.
As R
1, R
11Or by NR
4R
5The suitable example of formed heterocyclic group comprises for example pyridine radicals such as 3-or 4-pyridine radicals, piperidyl such as piperidines-1-base, 3-or 4-piperidyl, homopiperidinyl, piperazinyl such as 1-piperazinyl, high piperazinyl, morpholine-4-base, imidazole radicals, imidazolidinyl, pyrrole radicals or pyrrolidinyl, they are optional substituted, and for example coverlet replaces or be polysubstituted.When heterocyclic group when being substituted, this can be on one or more ring carbon atoms and/or when having theheterocyclic nitrogen atom on theheterocyclic nitrogen atom.Substituent example on ring carbon atom comprises for example C
1-4Alkyl such as CH
3C
3-6Cycloalkyl such as cyclopropyl are randomly further by C
1-4Alkyl replaces;
Wherein p is 1,2 or 3, preferred 1; CF
3Halogen; OH; NH
2-CH
2-NH
2-CH
2-OH; Piperidines-1-base; Or pyrrolidinyl.Substituent example on theheterocyclic nitrogen atom has for example C
1-6Alkyl; Acyl group, as R ' x-CO, wherein R ' x is H, C
1-6Alkyl or phenyl, optional by C
1-4Alkyl, C
1-4Alkoxyl or amino replacement the, for example formoxyl; C
3-6Cycloalkyl; C
3-6Cycloalkyl-C
1-4Alkyl; Phenyl; Phenyl-C
1-4Alkyl is as benzyl; Heterocyclic group, for example above those disclosed for example comprises the aromatic heterocyclic group of 1 or 2 nitrogen-atoms; Or formula α group
-R
21-Y’ (α)
R wherein
21Be C
1-4Alkylidene or by O C at interval
2-4Alkylidene and Y ' are OH, NH
2, NH (C
1-4Alkyl) or N (C
1-4Alkyl)
2
In formula (I), by O C at interval
2-4Alkylidene can be for example-CH
2-CH
2-O-CH
2-CH
2-.
In formula (I), when the substituent group on ring nitrogen was heterocyclic group, it can be heteroatomic 5 or 6 yuan of saturated, the unsaturated or heteroaromatics that comprise 1 or 2 hetero atom, are preferably selected from N, O and S.Example comprises for example 3-or 4-pyridine radicals, piperidyl such as piperidines-1-base, 3-or 4-piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, pyrimidine radicals, morpholine-4-base, imidazole radicals, imidazolidinyl, pyrrole radicals or pyrrolidinyl.
In formula (I), work as R
aBe the C that replaces
1-4During alkyl, substituent group is preferably endways on the carbon atom.
When ring A was substituted, it can be single replacement or polysubstituted, preferably mono-substituted, and substituent group can be selected from for example halogen, OH, C
1-4Alkoxyl such as OCH
3, C
1-4Alkyl such as CH
3, NO
2, CF
3, NH
2, NHC
1-4Alkyl, N (two-C
1-4Alkyl)
2And CN.For example, ring A can be the group of following formula
Wherein
R
dBe H; C
1-4Alkyl; Or halogen; And
R
eBe OH; NO
2NH
2NHC
1-4Alkyl; Or N (two-C
1-4Alkyl)
2
Preferred R
dAt 1; Preferred R
eAt 3.
Work as R
eHave by CR
xR
yThe CH that replaces
2The time, it preferably is loaded with the CH of Y
2
As R
1, R
11Or by NR
4R
5The example of formed heterocyclic group comprises for example formula (γ) group
Wherein
Ring D is 5,6 or 7 yuan of saturated, unsaturated or aromatic rings;
X
bBe-N-,-C=or-CH-;
X
eBe-N=,-NR
f-,-CR
f'=or-CHR
f'-, be R wherein
fBe as mentioned at the substituent group shown in the theheterocyclic nitrogen atom, and R
f' be as mentioned at the substituent group shown in the ring carbon atom;
C
1And C
2Between key be saturated or unsaturated;
C
1And C
2Be optional by the carbon atom that one or two substituent group replaced independently of one another, wherein said substituent group is selected from above at those substituent groups shown in the ring carbon atom; And
C
3And X
bBetween line and C
1And X
bBetween line represent respectively and obtain 5,6 or 7 yuan of required carbon numbers of ring D.
Preferred formula (γ) group is that its medium ring D formation is optional as shown by 1 of C-and/or N-replacement, the group of 4-piperazinyl ring.
The representative example of formula (γ) group has for example 3-or 4-pyridine radicals; Piperidines-1-base; 1-N-(C
1-4Alkyl)-or-(ω-hydroxyl-C
1-4Alkyl)-the 3-piperidyl; Morpholine-4-base; Imidazole radicals; Pyrrolidinyl; The 1-piperazinyl; 2-C
1-4Alkyl-or-C
3-6Cycloalkyl-1-piperazinyl; 3-C
1-4Alkyl-or-C
3-6Cycloalkyl-1-piperazinyl; 2,2-or 3,5-or 2,5-or 2,6-two (C
1-4Alkyl)-the 1-piperazinyl; 3,4,5-three-(C
1-4Alkyl)-the 1-piperazinyl; 4-N-(C
1-4Alkyl)-or-(ω-hydroxyl-C
1-4Alkyl)-or-(ω-dimethylamino-C
1-4Alkyl)-the 1-piperazinyl; 4-N-pyridin-4-yl-1-piperazinyl; The 4-N-phenyl-or-C
3-6Cycloalkyl-1-piperazinyl; 4-N-(C
1-4Alkyl)-or-(ω-hydroxyl-C
1-4Alkyl)-3-C
1-4Alkyl-or-3,3-two (C
1-4Alkyl)-the 1-piperazinyl; 4-N-(1-C
1-4Alkyl-C
3-6Cycloalkyl)-the 1-piperazinyl; 4-N-formoxyl-1-piperazinyl; 4-N-pyrimidine-2-base-1-piperazinyl; 4,7-diaza-spiro [2.5] octane-7-base or 4-N-C
1-4The high piperazinyl of alkyl-1-.
Work as R
1Or R
11And/or R
2, R
3, R
12Or R
13When comprising optional substituted amino and maybe can form the heterocyclic group of acid-addition salts, formula (I) chemical compound can exist as the addition salts form that forms with for example organic or inorganic acid (for example hydrochloric acid, acetic acid) with free form or with salt form.
Be appreciated that formula (I) chemical compound can exist with the form of optical isomer, racemate or diastereomer.For example, as R
1, R
11Or by NR
4R
5It is asymmetric being loaded with substituent ring carbon atom in the formed heterocyclic group, and it can have D-or L-configuration.Should be appreciated that the present invention includes all enantiomers and their mixture.Similarly consider to be applied to present the raw material of described asymmetric carbon atom.
In formula (I) chemical compound, unite preferred following implication individually or with any Asia:
1.R
aBe H or CH
3
2.R
bBe H;
3. ring A is unsubstituted; Or at 7 by methyl substituted;
4. preferred as by NR
4R
5Formed heterocyclic group for example has: the piperazine that is replaced by N--1-base is randomly for example replaced by following group N-: C
1-4Alkyl, ω-hydroxyl-C
1-4Alkyl, ω-dimethylamino-C
1-4Alkyl, C
5-6Cycloalkyl, C
1-4Alkyl-C
5-6Cycloalkyl comprises the aromatic heterocyclic group of 1 or 2 nitrogen-atoms, for example pyridine radicals or pyrimidine-2-base or 4,7-diaza-spiro [2.5] octane-7-base; Or as hereinbefore defined and/or the optional formula β group that is replaced by C-, for example by CH
3Replace, for example 2 and/or 3 and/or 5 and/or 6 and/or 2,2 or 3,3 by CH
3Replace, perhaps by
Replace, for example at the two or three-digit quilt
Replace; Optional piperidines-1-the base that is replaced by C-, for example at 4 by NH
2,-CH
2-NH
2Or piperidines-1-base replaces, perhaps is substituted at 3, for example by OH or NH
2Replace; Perhaps choose wantonly at 3 by OH or NH
2The pyrrolidinyl that the C-of institute replaces;
5.R
1And R
11Be 1-N-methyl-piperidin-4-yl independently of one another; 4-methyl-piperazine-1-base; 4-methyl isophthalic acid-Gao piperazinyl; 4-(2-hydroxyethyl)-piperazine-1-base; Or-X '-C
1,2 or 3-alkylidene-NR
7R
8, wherein X ' is straight key, O or NH;
6. in formula (a) group, R
2And R
3Each is H, perhaps R naturally
2And R
3One of be that H and another are F, Cl, CH
3, OCH
3Or CF
3
7. in formula (a) group, R
1And R
2Each is H, perhaps R naturally
1And R
2One of be that H and another are F, Cl, CH
3, OCH
3Or CF
3Preferred R
2Be H and R
1At 5,6,7 or 8, preferably at 6;
8. in formula (b) group, R
12And R
13Each is H naturally; Perhaps R
12And R
13One of be that H and another are F, Cl, CH
3, OCH
3Or CF
3Preferred R
13Be H and R
12At 7;
9. in formula (b) group, R
12And R
13Each is H naturally; R
11Be 4,7-diaza-spiro [2.5] octane-7 base; Or replaced by methyl or ethyl and choose wantonly at 4 by methyl substituted piperazine-1-base at 3.
Formula (I) chemical compound is known, can be as this area be disclosed, for example as US6, and 645,970, preparing like that described in the EP1490355A1, these two pieces of documents are incorporated herein by reference.They can as disclosed or be similar to the method described in these lists of references and prepare.
Preferred formula (I) chemical compound has 3-(1.H.-indol-3-yl)-4-[2-(4-methyl-piperazine-1-yl)-quinazoline-4-yl of free form or pharmaceutical acceptable salt]-pyrroles-2,5-diketone (compd A hereinafter referred to as), 3-(1.H.-indol-3-yl)-4-[2-(piperazine-1-yl)-quinazoline-4-yl]-pyrroles-2,5-diketone (compd B hereinafter referred to as), 3-[3-(4,7-diaza-spiro [2.5] octane-7-yl)-isoquinolyl-1]-4-(7-Methyl-1H-indole-3-yl)-pyrroles-2,5-diketone (Compound C), the 3-of acetate form (1.H.-indol-3-yl)-4-[2-(4-methyl-piperazine-1-yl)-quinazoline-4-yl for example]-pyrroles-2, the 5-diketone, or 3-[3-(4,7-diaza-spiro [2.5] octane-7-yl)-isoquinolyl-1]-4-(7-Methyl-1H-indole-3-yl)-pyrroles-2, the 5-diketone.
Other pkc inhibitor is a formula IIa compound or pharmaceutically acceptable salt thereof used according to the present invention,
Wherein
R
1aBe
Wherein s ' is 0 and R '
12Be hydrogen or C
1-4Alkyl; Perhaps s ' is 1 and R '
12Be pyridine radicals,
Preferred 2-pyridine radicals, and
R '
1aBe hydrogen or C
1-4Alkyl.
Formula IIa chemical compound can exist with the form of hydrate or solvate.
Even be more preferably 3-(1-Methyl-1H-indole-3-yl)-4-[1-{ (1-pyridine-2-ylmethyl)-piperidin-4-yl }-the 1H-indol-3-yl]-pyrroles-2,5-diketone (Compound D) or 3-(1-Methyl-1H-indole-3-yl)-4-[1-(piperidin-4-yl)-1H-indol-3-yl]-pyrroles-2,5-diketone (compd E) or its pharmaceutically useful salt, hydrate or solvate.
Formula IIa chemical compound can come synthetic as known in the art like that, and for example as US5, coming like that described in 545,636 is synthetic.
In a series of further concrete or alternate embodiments, the present invention also provides:
1. treatment, prevent or delay ophthalmic and disorder, particularly relate to the ophthalmic and the disorderly method of inflammatory and/or new vessels incident, perhaps delay the method for their development, as mentioned below, described method comprises that pkc inhibitor to curee's administering therapeutic effective dose of getting involved is suc as formula I chemical compound or formula IIa chemical compound.
" new vessels formation " (being also referred to as " new vessels incident ") includes but not limited to that retinal neovascularization forms, cornea rebirth blood vessel forms and choroidal neovascularization forms as herein defined.
Include but not limited to degeneration of macula (AMD) as defined among the application " relating to the ophthalmic or the disorder of inflammatory and/or new vessels incident ", diabetic eye disease or disorder, uveitis, optic neuritis, edema oculi, the eye angiogenesis, the ischemic retinal disease, anterior ischemic optic neuropathy AION, optic neuropathy and neuritis, macular edema, cystoid macular edema (CME), retinal diseases or disorderly as detachment of retina, retinitis pigmentosa (RP), recessive macular dystrophy, the special yolk sample of bass retinal degeneration (Best ' s vitelliform retinal degeneration), sick and other hereditary retinal dystrophy of Lay uncle congenital amaurosis, Suo Si is than fundus dystrophy (Sorsby ' s fundus dystrophy), pathologic myopia, retinopathy of prematurity (ROP), leber hereditary optic neuropathy, corneal transplantation or corneal refractive operation, keratoconjunctivitis or xerophthalmia.
" AMD " as defined herein includes but not limited to age-related macular degeneration (ARAMD).ARMD comprises its dryness form (dryness ARMD) and moist form (wet ARMD).
Include but not limited to that as " diabetic eye disease or the disorder " that defines among the application diabetic retinopathy (DR), diabetic macular edema (DME), diabetic proliferative retinopathy become (PDR) and uveitis.
Include but not limited to anterior uveitis, middle uveitis, back uveitis and panuveitis as " uveitis " that defines among the application.
On the other hand, the invention provides:
2. the pkc inhibitor that is used for 1 defined method above is suc as formula (I) or (IIa) chemical compound, preferred compound A, B, C, D or E or its officinal salt;
3. the pkc inhibitor that is used for preparing the pharmaceutical composition that uses in 1 defined method above is suc as formula (I) or (IIa) chemical compound, preferred compound A, B, C, D or E or its officinal salt;
4.PKC inhibitor is suc as formula (I) or (IIa) chemical compound, preferred compound A, B, C, D or E or its officinal salt purposes in the preparation medicine, described medicine is used for the treatment of, prevents or delays ophthalmic and disorder, particularly relates to the ophthalmic of inflammatory and/or new vessels incident and disorderly or delay its development, particularly as hereinbefore defined age-related macular degeneration, retinal diseases or disorder or diabetic eye disease or disorder.
5. be used for the pharmaceutical composition that uses in 1 defined method above, it comprises pkc inhibitor suc as formula (I) or (IIa) chemical compound, preferred compound A, B, C, D or E or its officinal salt and comprise one or more pharmaceutically acceptable diluents or the carrier that is used for this.
Formula (I) chemical compound can be used with free form or the pharmaceutical acceptable salt pharmaceutical acceptable salt shown in as mentioned.This class salt can prepare in a usual manner, and they demonstrate the activity with the free cpds same levels.
Formula (IIa) chemical compound can be with free form or with hydrate, solvate or salt form, for example use with pharmaceutical acceptable salt.This class hydrate, solvate and salt can prepare in a usual manner, and they demonstrate the activity with the free cpds same levels.
The effect of pkc inhibitor, for example the indicated as mentioned ophthalmic that relates to inflammatory or new vessels incident of treatment and the effect in the disorder can the animal testing method and clinical, for example prove according to hereinafter described method.
The A.PKC inhibitor can be determined in allogeneic mixed lymphocyte reaction (MLR) is analyzed the binding affinity of individual people PKC.MLR analyzes the mice that can analyze according to known method, for example people MLR, for example carries out as disclosed method among the EP1337527A1, and the content of relevant MLR analysis is incorporated herein by reference.
B. in the body
Can for example in following animal model, establish the effect in the disorder of described eye:
1) the heritability animal model of retinal degeneration, for example the rd mice (as people such as Li, Invest.Ophthalmol.Vis.Sci.2001; Described in the 42:2981-2989), Rpe65-defective mice (people such as VanHooser, PNAS 2000; 97:8623-8628), the RCS rat (people such as Faktorovich, Nature 1990; 347:83-86), the rds mice (people such as Ali, Nature Genetics 2000,25:306-310), the rcd1 dog (people such as Suber, PNAS 1993; 90:3968-3972)
2) inductive in the following way experimental retinal degeneration
-mice (as people such as Wenzel, Invest.Ophthalmol.Vis.Sci.2001; Described in the 42:1653-1659) or rat (people such as Faktorovich, J.Neurosci:1992; Light contact method 12:3554-3567)
-use N-methyl-N-nitrosourea (people such as Kiuchi, Exp.Eye Res.2002; 74:383-392) or sodium iodide (Sorsby ﹠amp; Harding, Vision Res.1962; 2:139-148).
3) optic nerve (ON) injury experiment model
-by at mice (people such as Levkovitch-Verbin, Invest.Ophthalmol.Vis.Sci.2000; 41:4169-4174) and rat (Yoles and Schwartz, Exp.Neurol.1998; Weigh ON 153:1-7) wounded
-by in rat, carry out the ON Transection (as people such as Martin, Invest.Ophthalmol.Vis.Sci.2002; 43:2236-2243, people such as Solomon, J.Neurosci.Methods 1996; Described in the 70:21-25)
-by the colligation of eye blood vessel (as people such as Lafuente, Invest.Ophthalmol.Vis.Sci.2001; Described in the 42:2074-2084) or anterior chamber's cannulation (people such as Buchi, Ophthalmologica 1991; 203:138-147) back experimental instantaneous (acute) retinal ischemia in rat
-by at rat (people such as Stokely, Invest.Ophthalmol.Vis.Sci.2002; 43:3223-3230) or rabbit (people such as Takei, Graefes Arch.Clin.Exp.Ophthalmol 1993; Intraocular injection endothelin-1 231:476-481)
4) choroidal neovascularization of induced with laser forms (CNV)
Laser directly pass crystalline lens to retina, destroy Bruch's membrane and cause and pass hole to the inner amphiblestroid new vessels of burning by choroid and form and reply.Administered compound before closing on laser irradiation or after the just sharp irradiation forms new vessels and carried out 7-14 days.When finishing at this moment, animal is sentenced euthanasia, measure the area of new vessels film.(referring to people such as Kwak, (2000) " VEGF is the important stimulus thing that choroidal neovascularization forms model " (VEGF is Major Stimulator inModel of Choroidal Neovascularization) .Investigative Ophthalmology andVision Science.41 (10); 3158-64)
5) experimental autoimmune uvea retinitis
In rat by causing uveitis with cattle retinal antigen immune.Because effect T-lymphocyte responses, retina is irreversibly damaged, as the clinical severity by ophthalmia disease and/or histology are measured.Disease phenotype is appearance in 10-12 days after immunity, reached maximum at 1-2 days after a while.From the duration of immunity administered compound, allow it to carry out 14 days.The clinical evaluation rat since the 10th day to the 14th day.When the phase finishes at this moment, rat is sentenced euthanasia, eye is carried out histology's sign.(referring to people such as Wacker WB, (1977) " tentative allergia uvea eye.From bovine retina, separate solubility and cause uveitis antigen and sign and location " (Experimentalallergic uveitis.Isolation; characterization, and localization of a solubleuveitopathogenic antigen from bovine retina) .J Immunol.119:1949-1958)
C. clinical experiment
Suitable clinical research is for example randomized, double-blind in age-related macular degeneration, diabetic retinopathy, diabetic macular edema (DME) or uveitis patient, the clinical research of placebo.This class research also can be suitable for relatively adopting formula I or the IIa chemical compound effect of Combination as monotherapy or described chemical compound and second kind of drug substance of active component.
For example, 200 patients that are diagnosed as DME accept daily dose for for example 50,200 or the test compounds of 400mg suc as formula I or IIa compound or pharmaceutically acceptable salt thereof such as compd A, B, C, D or E or placebo, every day twice oral administration.Estimated the variation percentage ratio of macular edema at 3rd month, compare with baseline.Thereby, for example, measure macula lutea thickness by optical coherence tomography (OCT), calculate edema thickness by the average thickness in the center subdomain of six-radial scan figure, correction is 175 microns, represents normal macula lutea thickness.Adopt test compounds to observe beneficial effect.
On the other hand, 200 AMD patients accept daily dose for for example 50,200 or the test compounds of 400mg suc as formula I or IIa compound or pharmaceutically acceptable salt thereof such as compd A, B, C, D or E or placebo, every day twice oral administration.Estimated the variation percentage ratio of macular edema at 1st month, compare with baseline.Thereby, for example, measure macula lutea thickness by optical coherence tomography (OCT), calculate edema thickness by the average thickness in the center subdomain of six-radial scan figure, correction is 175 microns, represents normal macula lutea thickness.Adopt test compounds to observe beneficial effect.
On the other hand, 200 uveitis patients accept daily dose for for example 50,200 or the test compounds of 400mg suc as formula I or IIa compound or pharmaceutically acceptable salt thereof such as compd A, B, C, D or E or placebo, every day twice oral administration.Estimated the variation percentage ratio of ophthalmia disease at 2nd month, compare with baseline.Thereby for example, ophthalmia disease is estimated by specified clinician, and the severity of vitreous opacity is determined according to the scale of having set up.Adopt test compounds to observe beneficial effect.
According to the present invention, formula (I) and (IIa) chemical compound can use by any conventional route, particularly the enteral approach is for example used with the form of tablet or capsule; Perhaps the outer approach of gastrointestinal tract is for example used with the form of injectable solutions or suspensoid; Local approach is for example used with the form of washing liquid, gel, ointment or cream, perhaps uses with per nasal or suppository form.Comprise the formula (I) of free form or pharmaceutical acceptable salt and (IIa) pharmaceutical composition of chemical compound and at least a pharmaceutically suitable carrier or diluent can be in a usual manner, by preparing with pharmaceutically suitable carrier or mixing diluents.Be used for the active substance that Orally administered unit dosage forms contains for example about 0.1mg to 500mg.
Preferred compound for example is applied to skin by local application.Even preferred local application form is to be applied to eye.
Required daily dose will change according to for example seriousness of compound used therefor, host, mode of administration, symptom to be treated in implementing method of the present invention.In relatively large mammal (for example people), Orally administered indication daily dose is about 0.5mg extremely active component such as compd A, B or the C of about 2000mg scope, easily with for example every day of maximum four times separate doses or use with the slow release form.
Required dosage will change according to mode of administration, concrete symptom and Expected Results to be treated certainly.Usually, be instructed to obtain gratifying result with about 0.1 daily dose systemic administration to about 100mg/kg body weight.In relatively large mammal (for example people), the indication daily dose is about 0.5mg about 2000mg scope extremely, easily with for example every day of maximum four times separate doses or use with the slow release form.
Pkc inhibitor suc as formula (I) or (IIa) chemical compound can be used as the single-activity composition and use, perhaps be used for the treatment of with other or prevent ophthalmic and disorderly, particularly relate to ophthalmic and the disorderly material that inflammation and/or new vessels form and use.For example, they can be used in combination with anti-angiogenic inhibition medicine or staurosporine derivatives or its salt and/or S1P receptor stimulating agent or its salt.
Anti-angiogenic inhibition medicine can include but not limited to
(Verteporfin, United States Patent (USP) 5,095,030 and EP 3520076 in address),
(piperazine Jia Tani sodium), Retaane (NSC 24345), EVIZON
TM(lactic acid Squalamine), VEGF inhibitor (VEGF) as
(ranibizumab) or Vatalanib.
Staurosporine derivatives or its salt are for example addressed in EP 1131073B1, United States Patent (USP) 5,093,330, and the description of relevant staurosporine derivatives is incorporated herein by reference in these patents.
According to the present invention; preferred staurosporine derivatives comprises: N-(3-carboxypropanoyl)-staurosporin; N-benzoyl-staurosporin; N-TFA base-staurosporin; N-methylamino thiocarbonyl-staurosporin; N-phenylamino formoxyl-staurosporin; N-(3-nitro benzoyl)-staurosporin; N-(3-fluoro benzoyl)-staurosporin; N-tertbutyloxycarbonyl-staurosporin; N-(4-carboxylbenzoyl)-staurosporin; N-(3, the 5-dinitrobenzoyl)-staurosporin; N-alanyl-staurosporin; N-ethyl-staurosporin; N-carboxymethyl-staurosporin; the N-[(t-butoxycarbonyl amino)-acetyl group]-staurosporin; N-(2-glycyl)-staurosporin and their officinal salt.
The S1P receptor stimulating agent is the chemical compound of conduct to the agonist conducted signal of one or more phosphoric acid sphingol-1 receptors such as S1P1 to S1P5.Can for example cause with the agonist of S1P receptors bind that isomery trimer G-Protein Separation is G α-GTP and G β γ-GTP in the cell, and/or cause the phosphorylation of the receptor that agonist occupies to increase and downstream signal pathway/kinase activator.
The S1P receptor stimulating agent is the sphingol analog normally, 2-amino-propane-1 of replacing of 2-for example, and 3-glycol or 2-amino-propanol derivatives, for example:
-2-amino-2-myristyl-1, ammediol, especially preferably FTY720, i.e. 2-amino-2-[2-(4-octyl phenyl) ethyl] propane-1, the 3-glycol is free form or pharmaceutical acceptable salt example hydrochloric acid salt form, and is as follows:
-2-amino-2-{2-[4-(1-oxo-5-phenylpentyl) phenyl] ethyl } propane-1, the 3-glycol is free form or pharmaceutical acceptable salt example hydrochloric acid salt;
-2-amino-4-(4-oxygen in heptan base phenyl)-2-methyl-butanols is free form or pharmaceutical acceptable salt example hydrochloric acid salt, more especially R-enantiomer;
-phosphoric acid FTY720;
-mono phosphoric acid ester-[(R)-and 2-amino-2-methyl-4-(4-amoxy phenyl)-butyl] ester;
-2-amino-2-[4-(3-benzyloxy thiophenyl)-2-chlorphenyl] ethyl-propane-1,3-glycol and corresponding phosphate derivative thereof, be mono phosphoric acid ester-2-amino-2-[4-(3-benzyloxy thiophenyl)-2-chlorphenyl] ethyl-propyl group] ester.
-(2R)-2-amino-4-[3-(4-cyclohexyl oxygen Ji Dingji)-benzo [b] thiophene-6-yl]-2-methybutane-1-alcohol,
-2-amino-4-[4-(3-benzyloxy thiophenyl)-2-chlorphenyl]-2-methybutane-1-alcohol; Corresponding mono phosphoric acid ester-2-amino-4-[4-(3-benzyloxy thiophenyl)-2-chlorphenyl]-the 2-methyl butyl] ester; 2-amino-4-[4-(3-benzyloxy thiophenyl)-2-chlorphenyl]-2-ethyl butane-1-alcohol; With corresponding mono phosphoric acid ester-2-amino-4-[4-(3-benzyloxy thiophenyl)-2-chlorphenyl]-the 2-ethyl-butyl] ester;
-1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxy imino group)-ethyl]-2-ethyl-benzyl }-azetidine-3-formic acid or its prodrug.
When pkc inhibitor and other medicines are co-administered, the dosage of the chemical compound of using jointly will depend on the type of used concomitant medication, used concrete medicine or disease to be treated etc. certainly.Term " is used " or " combined administration " etc. is intended to include selected therapeutant to the using of single patient jointly as used herein, and is intended to comprise that material wherein is not necessarily by identical route of administration or the therapeutic scheme used in the identical time.
Pkc inhibitor suc as formula (I) or (IIa) chemical compound, preferred compound A, B, C, D or E can in photodynamic therapy (PDT), use, as use with light and in oxygen enriched environment photoactive substance use combination.
According to aforementioned content, the present invention provides on the other hand:
6. drug regimen comprises a) first kind of material, and it is a pkc inhibitor suc as formula (I) or (IIa) chemical compound, preferred compound A, B, C, D or E or its officinal salt, and b) as hereinbefore defined second kind of drug substance.
7. method as hereinbefore defined, this method comprise to be used as the pkc inhibitor of administering therapeutic effective dose concurrently or in turn jointly suc as formula (I) or (IIa) chemical compound, preferred compound A, B, C, D or E or its officinal salt and second kind of drug substance, those shown in as mentioned for example.
8. treat, prevent or delay the method for its development, described method comprises the drug regimen to the individual administering therapeutic effective dose of getting involved, described combination comprises a) first kind of material, it is a pkc inhibitor suc as formula (I) or (IIa) chemical compound, preferred compound A, B, C, D or E or its officinal salt, and b) staurosporine derivatives or its salt and/or S1P receptor stimulating agent or its salt, and randomly comprise pharmaceutically suitable carrier.
As hereinbefore defined be combined in the purposes of preparation in the medicine, described medicine is used for the treatment of, prevents or delays ophthalmic and disorder, particularly relates to the ophthalmic and the disorder of inflammatory and/or new vessels incident, perhaps delay their development, particularly age-related macular degeneration, retinal diseases or disorder or the diabetic eye disease or the disorder of definition as mentioned.
Use drug regimen of the present invention and produced useful effect, particularly synergism.For example, compare with monotherapy, the dosage of effect prolongation, side effect minimizing, individual drugs is reduced combined therapy and quality of life improves.Other benefit is the active component that can use than the present invention of low dosage combination, and for example, required dosage not only often still less and can perhaps can be used to reduce the generation of side effect with lower frequency applications.This expectation and demand with patient to be treated is consistent.
With regard to as above hereinafter described combination of the present invention, they can use or use in succession with any order simultaneously, for example use respectively or use as fixed combination.
Combination of the present invention comprises " complete medicine ", and it means a and two kinds of materials of b all can be independently or contain not the different fixing of commensurability composition by use and be combined in different time points and give.The each several part of " complete medicine box " then can for example interlock, promptly any each several part of " complete medicine box " be used with identical or different interval in different time points simultaneously or in chronological order.Preferred selection time is at interval so that the effect that is used in combination treatment disease or disease of each several part is higher than by using the effect that only any one component obtained.
The effective dose of each used combined partner capable can change according to the severity of used particular compound or pharmaceutical composition, mode of administration, disease to be treated, disease to be treated in the combination of the present invention.Therefore, select the dosage of combination of the present invention according to the multiple factor that comprises route of administration.Internist, clinician or veterinary with common skill can easily determine and leave for the effective dose that alleviates, resists or stop the required independent active component of disease development.Acquisition does not have the optimal accuracy of the activity component concentration in the toxic scope need be based on the scheme of active component for the kinetics of the availability of target site producing effect.
The 3-that preferred chemical compound of the present invention is free form or pharmaceutical acceptable salt (1.H.-indol-3-yl)-4-[2-(4-methyl-piperazine-1-yl)-quinazoline-4-yl]-pyrroles-2, the 5-diketone, 3-(1.H.-indol-3-yl)-4-[2-(piperazine-1-yl)-quinazoline-4-yl]-pyrroles-2, the 5-diketone, 3-[3-(4,7-diaza-spiro [2.5] octane-7-yl)-isoquinolyl-1]-4-(7-Methyl-1H-indole-3-yl)-pyrroles-2, the 5-diketone, the 3-of acetate form (1.H.-indol-3-yl)-4-[2-(4-methyl-piperazine-1-yl)-quinazoline-4-yl for example]-pyrroles-2, the 5-diketone, or 3-[3-(4,7-diaza-spiro [2.5] octane-7-yl)-isoquinolyl-1]-4-(7-Methyl-1H-indole-3-yl)-pyrroles-2, the 5-diketone.
Claims (10)
1. treatment or prevention of age-related macular degeneration, retinal diseases or disorder or diabetic eye disease or disorderly method, this method comprises that the curee to this class treatment of needs uses pkc inhibitor or its officinal salt of the formula (I) of effective dose
R
aBe H; C
1-4Alkyl; Or by OH, NH
2, NHC
1-4Alkyl or N (two-C
1-4Alkyl)
2The C that replaces
1-4Alkyl; And
R is formula (a) or (b) group
Wherein
R
1And R
11Each is heterocyclic group naturally; NR
4R
5, R wherein
4And R
5Form heterocyclic group with their bonded nitrogen-atoms;
R
2, R
3, R
12And R
13Be H, halogen, C independently of one another
1-4Alkyl, CF
3, OH, SH, NH
2, C
1-4Alkoxyl, C
1-4Alkylthio group, NHC
1-4Alkyl, N (two-C
1-4Alkyl)
2Or CN; And
Ring A is optional substituted;
Or the pkc inhibitor of formula (IIa) or its officinal salt
Wherein
R
1aBe
Wherein s ' is 0 and R '
12Be hydrogen or C
1-4Alkyl; Perhaps s ' is 1 and R '
12Be pyridine radicals, preferred 2-pyridine radicals, and
R '
1aBe hydrogen or C
1-4Alkyl.
2. according to the process of claim 1 wherein that diabetic eye disease or disorder are diabetic retinopathy or diabetic macular edema.
3. according to the method for claim 1 or 2, wherein pkc inhibitor is selected from 3-(1.H.-indol-3-yl)-4-[2-(4-methyl-piperazine-1-yl)-quinazoline-4-yl]-pyrroles-2,5-diketone, 3-(1.H.-indol-3-yl)-4-[2-(piperazine-1-yl)-quinazoline-4-yl]-pyrroles-2,5-diketone, 3-[3-(4,7-diaza-spiro [2.5] octane-7-yl)-isoquinolyl-1]-4-(7-Methyl-1H-indole-3-yl)-pyrroles-2,5-diketone and their officinal salt.
4. according to the method for claim 3, wherein pkc inhibitor is 3-(1.H.-indol-3-yl)-4-[2-(4-methyl-piperazine-1-yl)-quinazoline-4-yl of acetate form]-pyrroles-2, the 5-diketone, or 3-[3-(4,7-diaza-spiro [2.5] octane-7-yl)-isoquinolyl-1]-4-(7-Methyl-1H-indole-3-yl)-pyrroles-2, the 5-diketone.
5. according to the method for claim 1 or 2, wherein pkc inhibitor is selected from 3-(1-Methyl-1H-indole-3-yl)-4-[1-{ (1-pyridine-2-ylmethyl)-piperidin-4-yl }-the 1H-indol-3-yl]-pyrroles-2,5-diketone, 3-(1-Methyl-1H-indole-3-yl)-4-[1-(piperidin-4-yl)-1H-indol-3-yl]-pyrroles-2,5-diketone and officinal salt thereof.
6. according to the method for any aforementioned claim, wherein pkc inhibitor and second kind of medication combined using, described second kind of medicine is selected from anti-angiogenic depressant, staurosporine derivatives, S1P receptor stimulating agent and salt thereof.
7. the pharmaceutical composition that uses in each the method in claim 1-7, it comprises formula (I) or pkc inhibitor (IIa) or its officinal salt as defined in claim 1 and comprises one or more pharmaceutically acceptable diluents or carrier.
8. drug regimen comprises a) as defined in claim 1 formula (I) or (IIa) chemical compound; And b) is selected from the shared material of anti-angiogenic depressant, staurosporine derivatives, S1P receptor stimulating agent and salt thereof.
9. combination according to Claim 8, its Chinese style (I) chemical compound is selected from 3-(1.H.-indol-3-yl)-4-[2-(4-methyl-piperazine-1-yl)-quinazoline-4-yl]-pyrroles-2,5-diketone, 3-(1.H.-indol-3-yl)-4-[2-(piperazine-1-yl)-quinazoline-4-yl]-pyrroles-2,5-diketone, 3-[3-(4,7-diaza-spiro [2.5] octane-7-yl)-isoquinolyl-1]-4-(7-Methyl-1H-indole-3-yl)-pyrroles-2,5-diketone and officinal salt thereof.
10. according to the combination of claim 9, its Chinese style (I) chemical compound is 3-(1.H.-indol-3-yl)-4-[2-(4-methyl-piperazine-1-yl)-quinazoline-4-yl of acetate form]-pyrroles-2, the 5-diketone, or 3-[3-(4,7-diaza-spiro [2.5] octane-7-yl)-isoquinolyl-1]-4-(7-Methyl-1H-indole-3-yl)-pyrroles-2, the 5-diketone.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US82329806P | 2006-08-23 | 2006-08-23 | |
| US60/823,298 | 2006-08-23 | ||
| US60/914,899 | 2007-04-30 |
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| Publication Number | Publication Date |
|---|---|
| CN101505749A true CN101505749A (en) | 2009-08-12 |
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ID=40977599
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800304039A Pending CN101505749A (en) | 2006-08-23 | 2007-08-21 | Use of PKC inhibitors in particular indolylmaleimide derivatives in ocular diseases |
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| Country | Link |
|---|---|
| CN (1) | CN101505749A (en) |
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2007
- 2007-08-21 CN CNA2007800304039A patent/CN101505749A/en active Pending
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Open date: 20090812 |