Use of PKC inhibitors in transplantation.

The present invention relates to the use of a PKC inhibitor in the treatment or prevention of rejection of insulin-producing cells or tissues such as islet transplantation rejection, in particular pancreatic islet cell transplantation, or preventing or delaying of rejection of insulin- producing tissues such as transdifferentiated hepatocytes, for example for the treatment of diabetes.

Transplantation of an entire pancreas is a major surgery, requiring general anesthetic, long stay in hospital and carries associated surgical and anesthetic risks. Transplantation of islet cells is a less invasive procedure, requiring only a local anesthetic. The islet cells may be isolated from the pancreas of a donor and then injected through a thin needle into the recipient's umbilical vein in the abdomen or through a tube inserted into a vein to the liver. Once transplanted, the new islet cells make and release insulin.

In spite of numerous treatment options for treating or preventing these graft rejections, there is still the need to expand the armamentarium of available immunosuppressive drugs available to increase the long-term success rate of islet transplantation, i.e. to treat, prevent or delay islet transplant rejection.

The present invention provides the use of a PKC inhibitor, in particular an indolylmaleimide derivative, in preventing, treating or delaying islet transplantation rejection, in particular in case of diabetes or chronic pancreatitis, wherein the indolylmaleimide derivative is a compound of formula (I)

wherein R _a is H; Ci. ₄ alkyl; or C _1-4 alkyl substituted by OH, NH ₂ , NHC-^alkyl or N(di-C _1-4 alkyl) ₂ ; and

R is a radical of formula (a) or (b)

wherein each of Ri and Rn is a heterocyclic residue, NR ₄ R ₅ wherein R ₄ and R ₅ form together with the nitrogen atom to which they are bound a heterocyclic residue, each of R ₂ R ₃ , R ₁₂ and R ₁₃ , independently, is H, halogen, C _{1 4} alkyl, CF ₃ , OH, SH, NH ₂ , C _{1 4} alkoxy, C _{1 4} alkylthιo, NHC _{1 4} alkyl, N(Ui-C _{1 4} alkyl) ₂ or CN, and ring A is optionally substituted, or a pharmaceutically acceptable salt thereof

In formula (I), any alkyl or alkyl moiety m e g alkoxy may be linear or branched Halogen may be F, Cl, Br or I, preferably F or Cl Any aryl may be phenyl or naphthyl, preferably phenyl

By heterocyclic residue as R ₁ , or R ₁₁ , or formed by NR ₄ R ₅ , is meant a three to eight, preferably five to eight, membered saturated, unsaturated or aromatic heterocyclic ring comprising 1 or 2 heteroatoms, preferably selected from N, O and S, and optionally substituted

Suitable examples of heterocyclic residue as R ₁ , R ₁₁ or formed by NR ₄ R ₅ include e g pyridyl, e g 3- or 4-pyπdyl, pipeπdyl, e g pιperιdιn-1-yl, 3- or 4-pιpeπdyl, homopiperidyl, piperazinyl, e g 1 -piperazinyl, homopiperazinyl, morpholιn-4-yl, imidazolyl, imidazolidinyl, pyrrolyl or pyrrolidinyl, optionally substituted, e g mono- or polysubstituted When the heterocyclic residue is substituted, this may be on one or more ring carbon atoms and/or on a ring nitrogen atom when present Examples of a substituent on a ring carbon atom include e g C _{1 4} alkyl e g CH ₃ ,

CH,

C _{3 6} cycloalkyl e g cyclopropyl, optionally further substituted by C _{1 4} alkyl, ^{(CH2 )p} wherein p is 1 ,2 or 3, preferably 1 , CF ₃ , halogen, OH, NH ₂ , -CH ₂ -NH ₂ , -CH ₂ -OH, pιpeπdιn-1-yl, or pyrrolidinyl Examples of a substituent on a ring nitrogen atom are e g C _{1 6} alkyl, acyl, e g R' _x -C0 wherein R' _x is H, C _{1 6} alkyl or phenyl optionally substituted by C _{1 4} alkyl, C _{1 4} alkoxy or amino, e g formyl, C _{3 6} cycloalkyl, Cs βcycloalkyl-C-i ₄ alkyl, phenyl, phenyl-C-i ₄ alkyl e g benzyl,

a heterocyclic residue, e.g. as disclosed above, e.g. an aromatic heterocyclic residue comprising 1 or 2 nitrogen atoms; or a residue of formula α

-R ₂₁ - Y ^' (α wherein R ₂₁ is C-|. ₄ alkylene or C ₂ - ₄ alkylene interrupted by O and Y' is OH, NH ₂ , NH(C ₁ ^aIRyI) or N(C ₁ ^aIRyI) ₂ .

In formula (I) C ₂ - ₄ alkylene interrupted by O may be e.g. -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -.

In formula (I), when the substituent on a cyclic nitrogen is a heterocyclic residue, it may be a five or six membered saturated, unsaturated or aromatic heterocyclic ring comprising 1 or 2 heteroatoms, preferably selected from N, O and S. Examples include e.g. 3- or 4-pyridyl, piperidyl, e.g. piperidin-1-yl, 3- or 4-piperidyl, homopiperidyl, piperazinyl, homopiperazinyl, pyrimidinyl, morpholin-4-yl, imidazolyl, imidazolidinyl, pyrrolyl or pyrrolidinyl,

In formula (I), when R _a is substituted C _1-4 alkyl, the substituent is preferably on the terminal carbon atom.

When ring A is substituted, it may be mono- or polysubstituted, preferably monosubstituted, the substituent(s) being selected from the group consisting of e.g. halogen, OH, Ci_ ₄ alkoxy, e.g. OCH ₃ , d_ ₄ alkyl, e.g. CH ₃ , NO ₂ , CF ₃ , NH ₂ , NHd_ ₄ alkyl, N(di-C ₁ _ ₄ alkyl) ₂ and CN. For example, ring A may be a residue of formula

wherein

R _d is H; Ci_ ₄ alkyl; or halogen; and

R _e is OH; NO ₂ ; NH ₂ ; NHd_ ₄ alkyl; or N(di-C _1-4 alkyl) ₂ .

Preferably R _d is in position 1 ; preferably R _e is in position 3.

When R _c has a CH ₂ replaced by CR _x R _y , it is preferably the CH ₂ bearing Y.

Examples of heterocyclic residue as R ₁ , R ₁₁ , or formed by NR ₄ R ₅ include e.g. a residue of formula (γ)

wherein

- A -

the ring D is a 5, 6 or 7 membered saturated, unsaturated or aromatic ring,

X _b is -N-, -C= Or -CH-,

X _c is -N=, -NRr, -CR/= or -CHR/- wherein R _f ιs a substituent as indicated above for a ring nitrogen atom, and R/ is a substituent as indicated above for a ring carbon atom, the bond between C ₁ and C ₂ is either saturated or unsaturated, each of Ci and C ₂ , independently, is a carbon atom which is optionally substituted by one or two substituents selected among those indicated above for a ring carbon atom, and the line between C ₃ and X _b and between C ₁ and X _b , respectively, represents the number of carbon atoms as required to obtain a 5, 6 or 7 membered ring D

A preferred residue of formula (γ) is one wherein the ring D forms a 1 ,4-pιperazιnyl ring optionally C- and/or N-substituted as indicated

Representative examples of a residue of formula (γ) are e g 3- or 4- pyπdyl, pιperιdιn-1 -yl; 1 - N-(C ₁ ^aIRyI)- or -(ω-hydroxy-Ci. ₄ alkyl)-3-pιperιdyl, morpholιn-4-yl, imidazolyl, pyrrolidmyl, 1- piperazinyl, 2-C^alkyl- or -Cs-ecycloalkyl-i -piperazinyl ,3-C ₁ - ₄ alkyl- or -C _{3 6} cycloalkyl-1- piperazinyl, 2,2- or 3,5- or 2,5- or 2,6-dι(Ci ₄ alkyl)-1-pιperazιnyl, 3,4,5-tπ-(Ci ₄ alkyl)-1 - piperazmyl, 4-N-(C ₁ _ ₄ alkyl)- or -(co-hydro Xy-C _{1 4} alkyl)- or - piperazinyl, 4-N-pyrιdιn-4-yl-1 -piperazinyl, 4-N-phenyl- or -Cs-ecycloalkyl-i -piperazinyl, 4-N- (C _{1 4} alkyl)- or -(ω-hydroxy-C^alkyO-S-d ₄ alkyl- or -3,3— dι(C _1-4 alkyl)-1 -piperazinyl, 4-N-(I-C ₁ . ₄ alkyl-C _{3 6} cycloalkyl)-1 -piperazinyl, 4-N-formyl-1 -piperazinyl, 4-N-pyπmιdιn-2-yl-1 -piperazinyl, 4,7-dιaza-spιro[2 5]oct-7-yl or 4-N-C^alkyl-i-homopιperazιnyl

The compounds of formula (I) may exist in free form or in salt form, e g addition salts with e g organic or inorganic acids, for example, hydrochloric acid, acetic acid, when R ₁ or R ₁₁ and/or R ₂ R ₃ , R ₁₂ or R ₁₃ comprises an optionally substituted amino group or a heterocyclic residue which can form acid addition salts

It will be appreciated that the compounds of formula (I) may exist in the form of optical isomers, racemates or diastereoisomers For example, a ring carbon atom bearing a substituent in the heterocyclic residue as R ₁ , R ₁₁ or formed by NR ₄ R ₅ is asymmetric and may have the D- or L- configuration It is to be understood that the present invention embraces all enantiomers and their mixtures Similar considerations apply in relation to starting materials exhibiting asymetric carbon atoms as mentioned

In the compounds of formula (I), the following significances are preferred individually or in any sub-combination:

1 . R _a is H or CH ₃ ;

2. R _b is H;

3. Ring A is unsubstituted; or is substituted by methyl in position 7;

4. Preferred heterocyclic residue as formed by NR ₄ R ₅ is e.g. piperazin-1-yl optionally N- substituted, e.g. by C _1-4 alkyl, π-hydroxy-C ₁ - ₄ alkyl, D-dimethylamino-Ci- ₄ alkyl, C ₅ . ₆ cycloalkyl, C-ualkyl-Cs-βcycloalkyl, an aromatic heterocyclic residue comprising 1 or 2 nitrogen atoms, e.g. pyridyl or pyrimidin-2-yl or 4,7-diaza-spiro [2.5] oct-7-yl; ora residue of formula β as defined above and/or optionally C-substituted, e.g. by CH ₃ e.g. in

positions 2, and/or 3 and/or 5 and/or 6 and/or 2,2 or 3,3 or by ^CH≥ , e.g. in position 2 or 3; piperidin-1 -yl optionally C-substituted, e.g. in position 4, by NH ₂ , -CH ₂ -NH ₂ or piperidin-1 -yl, or in position 3, e.g. by OH or NH ₂ ; or pyrrolidinyl optionally C-substituted in position 3 by OH or NH ₂ ;

5. Each of R ₁ and Rn, independently, is 1-N-methyl-piperidin-4-yl; 4-methyl-piperazin-1-yl; 4-methyl-1 -homopiperazinyl; 4-(2-hydroxyethyl)-piperazin-1 -yl; or -X'-C _{1 2 or 3} -alkylene-NR ₇ R ₈ wherein X' is a direct bond, O or NH;

6. Ri is piperazin-1-yl optionally substituted , e.g. 1-N-methyl-piperidin-4-yl; and Rn is 4,7- diaza-spiro [2.5] oct-7 yl;

7. In the residue of formula (a) either each of R ₂ and R ₃ is H or one of R ₂ and R ₃ is H and the other is F, Cl, CH ₃ , OCH ₃ or CF ₃ ;

8. In the residue of formula (a) either each of Ri and R ₂ is H or one of R ₁ and R ₂ is H and the other is F, Cl, CH ₃ , OCH ₃ or CF ₃ ; preferably R ₂ is H and R ₁ is in position 5, 6, 7 or 8, preferably in position 6;

9. In the residue of formula (b) each of R ₁₂ and R ₁₃ is H; or one of R ₁₂ and R ₁₃ is H and the other is F, Cl, CH ₃ , OCH ₃ or CF ₃ ; preferably R ₁₃ is H and R ₁₂ is in position 7;

10. In the residue of formula (b), each of R ₁₂ and R ₁₃ is H; R ₁₁ is 4,7-diaza-spiro [2.5] oct-7 yl; or piperazin-1-yl substituted in position 3 by methyl or ethyl and optionally in position 4 by methyl.

The compounds of formula (I) are known and may be prepared as disclosed in the art, e.g. as described in US6,645,970, EP1490355A1 , which are incorporated herein by reference.

They may be prepared as disclosed or by analogy to the procedures described in these references

Preferred compounds of formula (I) are 3-(7 /-/ -ιndol-3-yl)-4-[2-(4-methyl-pιperazιn-1-yl)- quιnazolιn-4-yl]-pyrrole-2,5-dιone (referred to hereinafter as Compound A), 3-(7 /-/ -ιndol-3- yl)-4-[2-(pιperazιn-1 -yl)-quιnazolιn-4-yl]-pyrrole-2,5-dιone (referred to hereinafter as Compound B), 3-[3-(4,7-dιaza-spιro[2 5]oct-7-yl)-ιsoquιnolιn-1-yl]-4-(7-methyl-1 H-ιndol-3-yl)- pyrrole-2,5-dιone (Compound C), in free form or in a pharmaceutically acceptable salt form,, e g the acetate salt of 3-(7 H -ιndol-3-yl)-4-[2-(4-methyl-pιperazιn-1 -yl)-quιnazolιn-4-yl]- pyrrole-2,5-dιone, or the acetate salt of 3-[3-(4,7-dιaza-spιro[2 5]oct-7-yl)-ιsoquιnolιn-1 -yl]-4- (7-methyl-1 H-ιndol-3-yl)-pyrrole-2,5-dιone

Other PKC inhibitors to be used in accordance of the invention are compounds of formula Na

wherein

wherein either s' is 0 and R'i ₂ is hydrogen or Ci ₄ alkyl, or s' is 1 and R' ₁₂ is pyπdyl, preferably 2-pyrιdyl, and

R'i _a is hydrogen or C _{1 4} alkyl, or a pharmaceutically acceptable salt thereof

The compounds of formula Ma may exist in form of hydrate or solvate

Even more preferred are 3-(1 -methyl-1 H-ιndol-3-yl)-4-[1 -{(1 -pyrιdιn-2-ylmethyl)-pιperιdιn-4- yl}-1 H-ιndol-3-yl]-pyrrole-2,5-dιone (Compound D), or 3-(1 -methyl-1 H-ιndol-3-yl)-4-[1-

(piperidin-4-yl)-1 H-indol-3-yl]-pyrrole-2,5-dione (Compound E), or a pharmaceutically acceptable salt, hydrate or solvate thereof.

The compounds of formula Ma may be synthesized as known in the art, e.g. as described in US 5,545,636.

In a series of further specific or alternative embodiments, the present invention also provides:

1. A method for treating, preventing or delaying rejection of insulin-producing cells or tissues such as islet transplantation rejection, or preventing or delaying rejection of insulin-producing tissues such as transdifferentiated hepatocytes, in particular in the case of a subject suffering from diabetes, e.g. type 1 diabetes, or pancreatitis, e.g. chronic pancreatitis, said method comprising administering to the affected subject a therapeutically effective amount of a PKC inhibitor, e.g. a compound of formula I or a compound of formula Na, preferably compound A, B, C, D or E, or a pharmaceutically acceptable salt thereof.

2. A method for treating, preventing or delaying diabetes, e.g. type 1 diabetes, or pancreatitis, e.g. chronic pancreatitis, said method comprising administering to an affected subject a therapeutically effective amount of a PKC inhibitor, e.g. a compound of formula I or a compound of formula Ha, preferably compound A, B, C, D, or E, or a pharmaceutically acceptable salt thereof,.

As herein defined, "islet transplantation" refers to islet cell autotransplantation and islet cell allotransplantation. Insulin-producing-tissues includes transdifferentiated hepatocytes as an example. These transdifferentiated hepatocytes, generated using gene activation and/or gene transfer methods, can be used for autotransplantation, allotransplantation or may be generated in situ in liver.

In another aspect the present invention provides:

3. A PKC inhibitor, e.g. a compound of formula (I) or (Na), preferably Compound A, B, C, D or E, or a pharmaceutically acceptable salt thereof, for use in a method as defined under 1 and/or 2 above;

4 A PKC inhibitor, e g a compound of formula (I) or (Ma), preferably Compound A, B, C, D or E, or a pharmaceutically acceptable salt thereof, for use in the preparation of a pharmaceutical composition for use in a method as defined under 1 and/or 2 above,

5 A pharmaceutical composition for use in a method as defined under 1 and/or 2 above comprising a PKC inhibitor, e g a compound of formula (I) or (Ma), preferably Compound A, B, C, D or E, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable diluents or carriers therefor

The compounds of formula (I) may be administered in free form or in pharmaceutically acceptable salt form e g as indicated above Such salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds

The compounds of formula (Ha) may be administered in free form or in form of hydrate, solvate or salt, e g in a pharmaceutically acceptable salt form Such hydrates, solvates and salts may be prepared in conventional manner and exhibit the same order of activity as the free compounds

Utility of the PKC inhibitor, e g in the prevention or treatment of islet transplantation rejection, as hereinabove specified, may be demonstrated in animal test methods as well as in clinic, for example in accordance with the methods hereinafter described

A Binding affinity of PKC inhibitors to individual human PKC may be determined in an Allogeneic Mixed Lymphocyte Reaction (MLR) assay MLR assay can be done according to known methods, e g mouse of human MLR assay, e g as disclosed in EP1337527A1 , the content regarding the MLR assay being incorporated herein by reference

B In vivo

Efficacy in the islet transplantation might be established for example as described in Nanji et al , American Journal of Transplantation 2004, 4 526-536), the content herein being incorporated by reference

Mice islet transplantation

The strain used: Adult C57BI/6 (H-2 ^b ), BALB/c (H.2 ^d ) and CBA/JCr (H-2 ^k ) male mice. C57BI/6 (H-2 ^b ) are rendered chemically diabetic by a single intravenous injection of streptozotocin (200mg/kg) Fully MHC-mismatched donor BALB/c islets are isolated by collagenase digestion (1 mg/ml) followed by Ficoll purification. Approximately 500 islets are transplanted under the left renal capsule of diabetic recipient mice. Allograft function is monitored by serial blood glucose measurements. Successful engraftment is defined by correction of the serum glucose level to < 8mmol/L by the third day post-transplant, and graft rejection is defined as a rise in serum glucose > 15 mmol/L for 2 consecutive days. Increases of islets graft survival are obtained in animals treated with a compound of formula I administered orally at a daily dose of 1 to 30 mg/kg.

Suitable clinical studies are, e.g., randomized, double-masked, placebo-controlled clinical studies in patients with diabetes. The beneficial effects on diabetes can be determined directly through the results of these studies which are known as such to a person skilled in the art. Such studies may also be suitable to compare the effects of a monotherapy using compounds of formula I or Ma as active ingredient or a combination of such compounds with a second drug substance.

For example, 50 ^! with type 1 diabetes receive the test compound, e.g. a compound of formula I or Ha, or a pharmaceutically acceptable salt thereof, e.g. Compound A, B, C, D or E, at a daily dosage of e.g. 50, 200 or 400 mg or placebo administered p.o. bid. A beneficial effect is observed with the test compounds.

According to the invention, the compounds of formula (I) and (Na) may be administered by any conventional route, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions, topically, e.g. in the form of lotions, gels, ointments or creams, or in a nasal or a suppository form. Pharmaceutical compositions comprising a compound of formula (I) and (Ha) in free form or in pharmaceutically acceptable salt form in association with at least one pharmaceutical acceptable carrier or diluent may be manufactured in conventional manner by mixing with a pharmaceutically acceptable carrier or diluent. Unit dosage forms for oral administration contain, for example, from about 0.1 mg to about 500 mg of active substance.

Preferably, the compound are administered topically, e.g. to the skin. A even more preferred form of topical administration is to the eye.

Daily dosages required in practicing the method of the present invention will vary depending upon, for example, the compound used, the host, the mode of administration, the severity of the condition to be treated. An indicated daily dosage for oral administration in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 2000 mg active ingredient, e.g. Compound A, B or C, conveniently administered, for example, in divided doses up to four times a day or in retard form.

The required dosage will of course vary depending on the mode of administration, the particular condition to be treated and the effect desired. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.1 to about 100 mg/kg body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 2000 mg, conveniently administered, for example, in divided doses up to four times a day or in retard form.

The PKC inhibitors, e.g. compounds of formula (I) or (Na), may be administered as the sole active ingredient or together with other drugs in immunomodulating regimens or other antiinflammatory agents, e.g. for the treatment or prevention of allo- or xenograft acute or chronic rejection or inflammatory or autoimmune disorders, or with other agents anti-diabetic drugs.

For example, the PKC inhibitors, e.g. compounds of formula (I) or (lla), may be used in combination with cyclosporines, or ascomycines or their immunosuppressive analogs or derivatives, e.g. cyclosporin A, ISA Tx247, FK-506, ABT-281 , ASM 981 ; an mTOR inhibitor, e.g. rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, or a rapalog, e.g. AP23573, AP23464, AP23675, AP23841 , TAFA-93, biolimus 7 or biolimus 9 etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; an EDG receptor agonist having accelerating lymphocyte homing properties, e.g. FTY 720 or an analogue thereof; leflunomide or analogs thereof; mizoribine; mycophenolic acid or a salt thereof, e.g. sodium salt; mycophenolate mofetil; 15-deoxyspergualine or analogs thereof; a JAK3 kinase inhibitor, e.g. N-benzyl-3,4-dihydroxy-benzylidene-cyanoacetamide D-cyano-(3,4-dihydroxy)- ]N-benzylcinnamamide (Tyrphostin AG 490), prodigiosin 25-C (PNU156804), [4-(4'- hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P131 ), [4-(3'-bromo-4'- hydroxylphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P154), [4-(3',5'-dibromo-4'- hydroxylphenyl)-amino-6,7-dimethoxyquinazoline] WHI-P97, KRX-21 1 , 3-{(3R,4R)-4-methyl-

3-[methyl-(7H-pyrrolo[2,3-d]pyπmιdιn-4-yl)-amιno]-pι perιdιn-1-yl}-3-oxo-propιonιtπle, in free form or in a pharmaceutically acceptable salt form, e g mono-citrate (also called CP- 690,550), or a compound as disclosed in WO 04/052359 or WO 05/066156, immunosuppressive monoclonal antibodies, e g , monoclonal antibodies to leukocyte receptors, e g , MHC, CD2, CD3, CD4, CD 1 1 a/CD18, CD7, CD25, CD 27, B7, CD40, CD45, CD58, CD 137, ICOS, CD150 (SLAM), OX40, 4-1 BB or their ligands, e g CD154, or other immunomodulatory compounds, e g a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e g an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e g CTLA4lg (for ex designated ATCC 68629) or a mutant thereof, e g LEA29Y, or other adhesion molecule inhibitors, e g mAbs or low molecular weight inhibitors including LFA-1 antagonists, Selectin antagonists and VLA-4 antagonists

For example, they may be used in combination with PPAR delta compound, for example an appropriate hypoglycemic thiazolidinedione derivative, e g ghtazone , non-ghtazone type PPARU agonists, especially N-(2-benzoylphenyl)-L-tyrosιne analogues, e g GI-262570, and JTT501 , insulin sensitivity enhancers , Or AT ₁ receptor antagonists, for example Diovan®, Co-Diovan® or a pharmaceutically acceptable salt thereof

The structure of the active agents identified by generic or tradenames may be taken from the actual edition of the standard compendium 'The Merck Index" or the Physician's Desk Reference or from databases, e g Patents International (e g IMS World Publications) or Current Drugs The corresponding content thereof is hereby incorporated by reference Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo

Insulin sensitivity enhancer restore impaired insulin receptor function to reduce insulin resistance and consequently enhance the insulin sensitivity

Where the PKC inhibitors are administered in conjunction with other drugs, dosages of the co-administered compound will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition to be treated, and so forth The terms 'coadministration" or 'combined administration' or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time

In accordance with the foregoing the present invention provides in a yet further aspect

5 A method as defined above comprising co-administration, e g concomitantly or in sequence, of a therapeutically effective amount of a PKC inhibitor, e g a compound of formula (I) or (Ma), preferably Compound A, B, C, D or E, or a pharmaceutically acceptable salt thereof, and a second drug substance, e g as indicated above

The administration of a pharmaceutical combination of the invention results in a beneficial effect, especially a synergistic effect For example combined treatment can result in surprising prolongation of efficacy, less side-effects, lower doses of the individual drugs or improved quality of life, compared to a monotherapy A further benefit is that lower doses of the active ingredients of the combination of the invention can be used, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side-effects This is in accordance with the desires and requirements of the patients to be treated

With respect to the combinations according to the present invention as described hereinbefore and hereinafter they may be used for simultaneous use or sequential use in any order, e g for separate use or as a fixed combination

The combinations according to the present invention comprises a "kit of parts" in the sense that both agents a and b can be dosed independently or by use of different fixed combinations with distinguished amounts of the components at different time points The parts of the "kit of parts" can then e g be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the "kit of parts" Preferably, the time intervals are chosen such that the effect on the treated disease or condition in the combined use of the parts is larger than the effect that would be obtained by use of only any one of the components

The effective dosage of each of the combination partners employed in the combination of the invention may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, the severity of the condition being treated Thus, the dosage regimen of the combination of the invention is

selected in accordance with a variety of factors including the route of administration. A physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the single active ingredients required to alleviate, counter or arrest the progress of the condition. Optimal precision in achieving concentration of the active ingredients within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the active ingredients' availability to target sites.