FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PHARMACEUTICAL COMOUNDS OF DIPEPTIDYL PEPTIDASE- 4 (DPP- 4) INHIBITORS AND MEGLITINTDES"
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: Mumbai Central, Mumbai - 400 008, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in
which it is to be formed.


FIELD OF INVENTION:
The present invention relates to Pharmaceutical Compounds comprising dipeptidyl peptidase-4 (DPP-4) inhibitor and meglitinides, processes for preparation of the same and • their uses as medicaments or in pharmaceutical composition, more particularly for the treatment of Type 2 diabetes. The Pharmaceutical Compound may be a salt, or a crystalline form of a salt or a co-crystal.
BACKGROUND OF THE INVENTION:
Diabetes mellitus (DM) is a growing health problem. Complications related to diabetes can lead to serious morbidity and significantly reduced life expectancy.
Type 2 diabetes is the most common form of the disease, accounting for 90-95% of all diagnosed cases of diabetes mellitus. The prevalence of Type 2 diabetes mellitus is increasing all over the world, especially in South Asia. India has largest population of diabetic patients. The International Diabetes Federation (IDF) estimates the number of people with diabetes in India will reach 80 million by the year 2025.
In Type 2 diabetes, the body does not produce enough insulin or the cells ignore the insulin which results in abnormalities in carbohydrates, fat and protein metabolism. Over time, high blood sugar levels can increase the risk for serious complications, including atherosclerosis, heart disease, stroke, hypertension, blindness, nerve damage and kidney damage.
There are at least seven different classes of agents used as monotherapy, or in combinations for the treatment of Type 2 diabetes mellitus. These include metformin, sulphonyl ureas, megiinifides, alpha-glucosidase inhibitors, thiazolidinediones (TZD), glucagon like peptide-I (GLP-1) agonists and insulin.
DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin. Incretins help the body produce more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed. These hormones are released throughout the day and levels are increased at meal times.

Although, a number of DPP-4 inhibitors have been described, all have limitations relating to potency, stability or toxicity.
Further, many conventional agents frequently exhibit reduced efficacy over time, leading to inadequate glycaemic control. Several of these agents are also associated with adverse effects that include weight gain, hypoglycemia and gastrointestinal distress.
Clinical studies have shown that two drug combinations of DPP-4 inhibitors with various other drugs are much more effective than one drug alone. A combination therapy of DPP-4 inhibitors with pharmaceutically active ingredient of diabetes metformin HC1, provides more effective treatment of Type II diabetes. The pharmaceutical combinations are disclosed in the patent application publications WO2009/099734, WO 2009/111200, WO2011/032912, the contents of which are herein incorporated by reference in their entirety.
However, the gastrointestinal adverse effect of metformin limits its tolerated dose. Further, all the above mentioned suggestions are related to pharmaceutical compositions, wherein DPP-4 inhibitors and metformin HC1 are not associated by chemical interactions in order to form one single entity or one single crystal structure. The art is also completely silent on combination of DPP-4 inhibitors with other antidiabetic agents.
There is a need therefore, for alternative therapies that can overcome the limitations associated with conventional anti-hyperglycemic medications. Also, there is a need in the art to develop pharmaceutical compounds of DPP-4 inhibitors to overcome the problem of bioavailability as well as to enhance the efficacy, by the synergistic action of API with any pharmaceutically active substance acting as an antidiabetic agent.
Combining two or more antidiabetic agents into a single tablet provides a potential means of delivering combination therapy without adding complexity of patients' daily regimens.
The selection of the components having complementary mechanism of action and compatible profiles is a key step in the design of a combination tablet.

Accordingly, one common class of drugs that are used to treat diabetes Type 2, in people whose blood sugar levels have not stayed within a target range, even though the people are being active and eating healthy foods are; meglitinides, aka "Glinides". Meglitinides, also known as the nonsulfonylurea secretagogues, are relatively new compared to the sulfonylureas. For example, Meglitinides are generically and specifically disclosed e.g. in the US patent 5216167 and in the US patent 4816484.
Meglitinides increase the amount of insulin produced by the pancreas, which lowers blood sugar. Meglitinides work by stimulating the pancreas to release insulin in response to a meal. It closes ATP-dependent potassium channels in functioning pancreatic beta cells. This blockade of potassium channels depolarizes the beta cells, which leads to opening of calcium channels resulting in influx of calcium. Increased intracellular calcium induces insulin secretion.
Meglitinides are approved for use alone and in combination with other oral diabetes drugs in people with Type 2 diabetes. The major effect of meglitinides is the reduction of after-meal blood glucose levels, which results in a reduction in HbAlc (an indicator of blood glucose control over the previous 2-3 months). However, these meglitinide are well-known to be only slightly soluble in water limiting their use in pharmaceutical formulations. Further, meglitinide have some role in treatment of diabetes, although their role is limited by cost and side-effects.
Therefore, it could be significant contribution by developing a new pharmaceutical compound comprising dipeptidyl peptidase-4 (DPP-4) inhibitors and meglitinides so as to combat the cost, side effects yet with increased efficiency.
Thus, it is an object of the present invention to provide new means for improving the properties of DPP-4 inhibitors, by providing new drugable forms of DPP-4 inhibitors. It is another object of the present invention to combine DPP-4 inhibitors with meglitinides, in order to lower the amount of meglitinides needed to provide an equivalent degree of antidiabetic effect.

SUMMARY OF THE INVENTION:
The present invention is directed to novel Pharmaceutical Compounds comprising a DPP-4 inhibitors and meglitinides, or pharmaceutically acceptable salts of each thereof, methods of preparing such Pharmaceutical Compounds, and methods of treating Type 2 diabetes with such Pharmaceutical Compounds. The Pharmaceutical Compound may be a salt, or a crystalline form of a salt or a co-crystal.
A "Pharmaceutical Compound" according to the present invention is a single chemical entity comprising two or more different elements that have a unique and defined chemical structure. Pharmaceutical Compounds consist of a fixed ratio of atoms that are held together in a defined spatial arrangement by ionic, covalent, hydrogen bonds, van der Waals forces or Π- π interactions. According to the present invention the elements of a Pharmaceutical Compound comprise DPP-4 inhibitors and meglitinides, water, ions, solvents, or co-formers.
In addition, the Pharmaceutical Compounds according to the present invention represent a "drugable form of DPP-4 inhibitors with meglitinides". A "drugable form" as used herein is defined as any form (salt, amorphous, crystal(of a salt), co-crystal, solution, dispersion , mixture, etc.) that DPP-4 inhibitors with meglitinides might take which still can be formulated into a pharmaceutical formulation usable as a medicament to treat a disease or a symptom.
Accordingly, the present invention provides novel synergistic Pharmaceutical Compounds of DPP-4 inhibitors with the group consisting of meglitinides.
The novel Pharmaceutical Compounds are relatively stable towards the moisture and humidity, thereby representing an amorphous or a crystalline form of Pharmaceutical Compound, thus enhancing the efficacy of the parent molecule in lower doses.
The Pharmaceutical Compounds according to the present invention are chracterised by powder X-ray, DSC thermogram and IR spectral data.

According to another aspect of the present invention, there is provided a process for preparing novel Pharmaceutical Compounds, the process comprising forming a solution of DPP-4 inhibitors and meglitinides in a suitable solvent at an appropriate temperature; promoting solid growth and collecting the solids, preferably by filtartion and drying at elevated temperature.
The DPP-4 inhibitors, as free base or as its physiologically acceptable salt may be, in any polymorphic form or in a mixture of any polymorphic forms.
According to another aspect of the present invention, there is provided novel Pharmaceutical Compounds prepared by a process according to the process described above. The process produces novel Pharmaceutical Compounds in high yield and purity.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising novel Pharmaceutical Compounds as described above, together with one or more pharmaceutically acceptable excipients.
According to another aspect of the present invention, there is provided novel Pharmaceutical Compounds as described above for use in medicine.
According to another aspect of the present invention, there is provided novel Pharmaceutical Compounds as described above for use in treating or preventing Type 2 diabetes.
According to another aspect of the present invention, there is provided the use of novel Pharmaceutical Compounds as described above for use in the manufacture of a medicament for treating or preventing Type 2 diabetes.
According to another aspect of the present invention, there is provided a method of treating or preventing Type 2 diabetes comprising administering to a patient in need thereof a therapeutically effective amount of novel Pharmaceutical Compounds as described above.

DETAILED DESCRIPTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and
appreciated.
Thus in one aspect, the present invention provides a stable novel Pharmaceutical Compound of DPP-4 inhibitor with meglitinide which is substantially non-hygroscopic and has good flow characteristics.
In another embodiment of this aspect of the invention, the DPP-4 inhibitor is selected
from the group consisting of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-
dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-amine;
(S)- 1 -[(3 -hydroxy- 1- adamantyl) amino] acetyl-2-cyano-pyrrolidine; (lS,3S,5S}-2-
[(2S)-2-amino-2-(3-hydroxy-l -adamantyl)acetyl]-2-azabicyclo[3.1.0] hexane-3-
carbonitrile; 8-[(3R)-3-aminopiperidin-l -yl]-7-(but-2-yn-l-yl)-3- methyl-l-[(4-methyl
quinazolin-2-yl)methyl] -3,7-dihydro-lH-purine-2,6-dione; 2-({6-[(3,R)-3-
arninopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydro pyr i mid in- 1(2H)-yl} methyl)
benzonitrile; (2S,4S)-4-Fluoro-l-[2-[[(lR,3S)-3-(lH-l,2,4-triazoI-l-
ylmethyl)cyclopentyl] amino]acetyl]-2-pyrrolidinecarbonitrile; (2S,4S)-1 -[(2S)-2-amino-3,3-b i s(4 -fluoropheny l)propanoy 1 ] -4- fluoropy rrol i d ine-2 -carbon itri 1 e; 1 - [N- [3 (R)-Pyrrolidinyl]glycyl]pyrrolidin-2(R)-yl boronic acid and l-{(25)-2-amino-4-[2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl]-4-oxobutyl}-5,5-difluoro piperidin-2-one.
In a class of this embodiment the DPP-4 inhibitor is, (2R)-4-oxo-[3-(trifluoromethyl)-5,6-
dihydro[l,2,4] triazolo [4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-amine;
(S)- 1 -[(3 -hydroxy- 1- adamantyl) amino]acetyl-2-cyano-pyrrolidine; {1S,3S,5S}-2-
[(25)-2-amino-2-(3-hydroxy-1 -adamantyl) acetyl]-2-azabicyclo[3.1.0]hexane-3-
carbonitrile or 8-[(3R)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3- methyl-l-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-lH-purine-2,6-dione. In a subclass of this class, the DPP-4 inhibitor is (2R)-4-oxo-[3-(trifluoromethyl)5,6-dihydro[l,2,4]triaolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-amine or

8-[(3R)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3- methyl-1-[(4-methylquinazoIin-2-yl)methyl]-3,7-dihydro-lH-purine-2,6-dione.
Co-formers to be combined with the DPP-4 inhibitors within the Pharmaceutical Compounds according to this invention are meglitinides. There are currently two meglitinides available— repaglinide (Prandin) and nateglinide(Starlix) which are herein incorporated by reference in their entirety.
In one embodiment the Pharmaceutical Compounds according to the present invention may be an amorphous or many crystalline forms.
Thus, in one embodiment of the present invention the novel Pharmaceutical Compound is selected from a group consisting of;
(2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl) butan -2-amine with nateglinide,
(2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triaoIo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl) butan-2-amine with repaglinide,
(S)-1 -[(3 -hydroxy-1 - adamantyl)amino]acetyl-2-cyano-pyrrolidine with nateglinide, (S)-1 -[(3 -hydroxy- l-adamantyl)amino]acetyl-2-cyano-pyrrolidine with repaglinide, (lS,3S,5S)2-[(2S)-2-amino-2-(3-hydroxy-l-adamantyl)acetyI]-2-azabicyclo[3.1.0]hexane-3-carbonitrile withnateglinide, (15,35',5S)-2-[(2,S)-2-amino-2-(3-hydroxy-l -adamantyl) acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile with repaglinide,
8-[(3R)-3-aminopiperidin-l -yl]-7-(but-2-yn-l -yl)-3-methyl-l -[(4-methylquinazolm-2-yl)methyl]-3,7-dihydro-lH-purine-2,6-dione with nateglinide, 8-[(3R)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3-methyl-l-[(4-methylqm'nazoIin-2-yl)methyl]-3,7-dihydro-lH-purine-2,6-dione with repaglinide, 2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyI-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl) benzonitrilewith nateglinide,
2-({6-[(3H)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl) benzonitrilewith repaglinide,
(2S,4S)-4-Fluoro-l-[2-[[(lR,3S)-3-(lH-l,2,4-triazol-l-ylmethyl)cyclopentyl]amino]acetyl]-2-pyrrolidine carbonitrile -with nateglinide,

(2S,4S)-4-Fluoro-l -[2-[[(lR,3S)-3-(lH-1,2,4-triazol-l-ylmethyl)cyclopenty1]amino]acety 1] -2-pyrro1idine carbonitri le-with repag] inide, (2S,4S)-l-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropym)lidine-2-carbonitrile-with nateglinide,
(2S,4S)-l-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrilewith repaglinide,
l-[N-[3(R)-Pyrrolidinyl]glycyl]pyrrolidin-2(R)-ylboronic acid - with nateglinide, 1 -[N-[3(R)-Pyrrolidinyl]glycyl]pyrrolidin-2(R)-ylboronic acid-with repaglinide, l-{(25)-2-amino-4-[2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl]-4-oxobutyl}-5,5-difluoropiperidin-2-one with nateglinide, and 1 - {(25)-2-am ino-4- [2,4-bis(trifluoromethyl)-5,8-dihydropyrido [3,4-d]pyrim idin-7(6H)-yl]-4-oxobutyl} -5,5-difluoropiperidin-2-onewith repaglinide.
In a preferred embodiment of the present invention the ratio of the components of DPP-4
inhibitor to meglitinide may be stoichiometric or non-stoichiometric. For example the
ratio may be 1:1, 1:1.5, 1.5:1,1:2 or 2:1.
In a preferred embodiment the novel Pharmaceutical Compound is of (2R)-4-oxo-[3-
(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yI]-l-(2,4,5-
trifluorophenyl)butan-2-amine with nateglinide.
The Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dmydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide possess, enhanced physical properties such as superior intrinsic dissolution, particularly compared to prior art forms of (2R)-4-oxo-[3-(trifluoro methyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine and nateglinide.
In the novel compound, the components (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yrj-l -(2,4,5- trifluoro phenyl) butan-2-am'me and nateglinide are present in an almost stoichiometric ratio. Therefore, the present invention relates to a Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide in which the components (2R)-4-oxo-[3-(trifluoromethyl)-5,6-

dihydro[1,2,4]triazolo[4,3-a]pyrazm-7(8H)-yl]-l -(2,4,5- trifluoro phenyl) butan-2-amine and nateglinide are present in a 1:] to 1:2, preferably in a 1:2 ratio.
A combination therapy of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with the well establised active ingredient nateglinide, of diabetes provides even more effective treatment of Type 2 diabetes.
The crystalline nature of novel Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide has been analyzed, characterized and differentiated by X-ray powder diffraction, a technique which is known per se.
The X-ray powder diffraction pattern of crystalline Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triaolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluoro phenyl) butan-2-amine with nateglinide was measured on a Rigaku Dmax 2200 advanced X-ray powder diffractometer with a copper-K-a radiation source.
In an embodiment, the crystalline Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyI)-5,6-dihydro[l,2!4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide has an XRD pattern comprising peaks at 5.24, 6.78, 11.22, 15.92, 18.18 and 20.88 °2θ ± 0.2°2θ. The crystalline compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluoro phenyl) butan-2-amine with nateglinide have an XRD pattern comprising further peaks at 10.12, 14.22, 23.34, 25.18 and 27.46°2θ • 0.2 °2θ9. Thus, typically, the crystalline Pharmaceutical Compound of (2R)-4-oxo-[3-(trifiuoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-I-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide has an XRD pattern comprising peaks at 5.24, 6.78, 10.12, 11.22, 14.22, 15.92, 18.18, 20.88, 23.34, 25.18 and 27.46 °2θ± 0.2 °2θ.
In another embodiment, Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-

amine with nateglinide of the present invention is characterized by having an X-ray powder diffraction spectrum as shown in Figure 1.
In an embodiment. Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4] triazolo[4,3-a]pyrazin-7(8H)-y)]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide of the present invention is characterized by having a DSC, exhibiting a significant peak at around 148°C.
In another embodiment, Pharmaceutical Compound of (2R)-4-oxo-[3-(trifiuoromethyl)-5,6-dihydro[1,2,4] triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide of the present invention is characterized by having a DSC as shown in Figure 2.
Infrared (FT-IR) spectra were obtained in a KBr disk using a Perkin Elmer FT-IR spectrophotometer Spectrum 1000 at resolution 4 cm"'. The characteristic absorption bands are expressed in cm"1.
In an embodiment, Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazoIo[4,3-a]pyrazin-7(8H)-yl]-l -(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide of the present invention is characterized by having characteristic IR spectra peaks at about 3307 cm-1, 2928 cm-1, 1698 cm-1, 1647 cm-1, 1526 cm-1, 1444 cm-1, 1278 cm-1, 1214 cm-1, 1144 cm-1,1015 cm-1, 934 cm-1, 843 cm-1, 759 cm-1,698 cm-1,668 cm-1 and 574 cm-1.
In another embodiment, Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyi)-5,6"dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-am'ine with nateglinide of the present invention is characterized by having an IR spectrum as shown in Figure 3.
In another aspect, the present invention provides a process for the preparation of
Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-
dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide.

The (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5- trifluoro phenyl) butan-2-amine and pharmaceutically acceptable salts thereof used in preparing the compound of the invention may be obtained by methods described in the US Patent No. 6,699,871 which are herein incorporated by reference in their entirety.
The (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5- trifluoro phenyl) butan-2-amine used as a starting material can be in any form, e.g. it can be a free base or a physiologically acceptable salt, in any polymorphic form or in a mixture of any polymorphic forms in a reaction solution, suspension, crude or in anhydrous, hydrated or solvated form. Preferably, (2R)-4-oxo-[3-(trif1uoromethyI)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine used is (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine base or (2R)-4-oxo-[3-(trifiuoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine phosphate.
The preparation of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro(l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-2,4,5- trifluoro phenyl) butan-2-amine phosphate monohydrate is disclosed in international patent publication WO 2005/0031335 published on January 13, 2005, the contents of which are herein incorporated by reference in their entirety.
The novel Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluorornethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide may be prepared by a process comprising; forming a solution of (2R)-4-oxo-[3-(trifluoromethyI)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yI]-l-(2,4,5-trifluoro phenyl) butan-2-amine and nateglinide in a suitable solvent at an appropriate temperature; promoting crystal growth and collecting the crystals, preferably by filtartion and drying at elevated temperature. The process produces novel Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyI)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine - nateglinide in high yield and purity.

Preferably, the solvent employed in this process are polar solvents and may be selected from alkyl ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone; cyclic ketones such as tetrahydrofuran and 1,4-dioxane; alcohols such as methanol, ethanol, isopropyl alcohol, butyl alcohol; esters such as ethyl acetate, methyl acetate, isopropyl acetate; ethers such as diethyl ether, dimethyl ether; other polar aprotic solvents such as acetonitrile; dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrroIidone; water and mixtures thereof. In a preferred embodiment the solvent is selected from the group consisting of acetone, acetonitrile, water and mixtures thereof.
The reaction is preferably performed at a temperature ranging from 20oC to 80°C. The
compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-
7(8H)-yl]-l -(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide is then allowed to
form, preferably by cooling to a temperature of about 20°C to about 40°C. The
Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-
dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide is then collected by filtration and drying. Preferably, the drying is performed in vacuo at elevated temperature ranging from 30-70°C.
In an embodiment, the process involves isolation of the novel Pharmaceutical Compound
of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-
(2,4,5- trifluoro phenyl) butan-2-aminewith nateglinide in a solvent-free media, thus
producing novel compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-
dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide free of solvents or having a negligible solvent content.
In another preferred embodiment the pharmaceutical compound according to the present invention is of 8-[(3/?)-3-aminopiperidin-l-yI]-7-(but-2-yn-l-yl)-3- methyl-l-[(4-methyl quinazolin-2-yl)methyl] -3,7-dihydro-l#-purine-2,6-dione with nateglinide with a molecular ratio of 1:1
The nature of novel Pharmaceutical Compound of 8-[(3i?)-3-aminopiperidin-I-yl]-7-(but-2-yn-]-yl)-3- methyl-l-[(4-methyI quinazolin-2-yl)methyl] -3,7-dihydro-l//-purine-2,6-

dione with nateglinide has been analyzed, characterized and differentiated by X-ray powder diffraction, a technique which is known per se.
The X-ray powder diffraction pattern of crystalline Pharmaceutical Compound of 8-[(3i?)-3-aminopiperidin-l -yl]-7-(but-2-yn-l-yl)-3- methyl-l-[(4-methyl quinazolin-2-yl)methyl] -3,7-dihydro-l/f-purine-2,6-dione with nateglinide was measured on a Rigaku Dmax 2200 advanced X-ray powder diffractometer with a copper-K-a radiation source.
In another embodiment, Pharmaceutical Compound of 8-[(37?)-3-aminopiperidin-l-y]]-7-(but-2-yn-l-yl)-3- methyl-l-[(4-methyl quinazolin-2-yI) methyl] -3,7-dihydro-lH-purine-2,6-dione with nateglinide of the present invention is characterized by having an X-ray powder diffraction spectrum as shown in Figure 4.
In a further aspect, the present invention provides a process for the preparation of Pharmaceutical Compound of 8-[(3i?)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yI)-3-methyl-l-[(4-methyl quinazolin-2-yl)methyl] -3,7-dihydro-lH-purine-2,6-dione with nateglinide comprising steps of; forming a solution of 8-[(3R)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3- methyl-l-[(4-methyl quinazoiin-2-yI)methyl] -3,7-dihydro-l/7-purine-2,6-dione and nateglinide in a suitable solvent or a solvent mixture at an appropriate temperature; collecting the resulting solids, preferably by filtartion and drying at elevated temperature. The process produces novel Pharmaceutical Compound of 8-[(3i?)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3- methyl-l-[(4-methyl quinazolin-2-yl)methyl] -3,7-dihydro-lH-purine-2,6-dione with nateglinide in high yield and purity.
The solvents usable in this process include water and/or organic solvents, preferably solvents selected from alky! ketones such acetone, methyl ethyl ketone, methyl isobutyl ketone, pentanone; cyclic ketones such as tetrahydrofuran and 1,4-dioxane; alcohols such as methanol, ethanol, isopropyl alcohol, 2-butanol; esters such as isobutyl acetate, butyl acetate, ethyl acetate; ethers such as diethyl ether, butylether, diisopropylether, methyl t-butyl ether, diisopropyl ether; polar aprotic solvents such as acetonitrile, dimethylformamide, dimethylcarbonate, non polar solvents such as dichloromethane, chloroform, chlorobenzene, hexane, toluene, and 1,1,1-trichloroethane. Preferably, the, solvent is selected from, alcohol, polar aprotic solvents and/or ethers..

The 8-[(3i?)-3-aminopiperidin-1-yl]-7-(but-2-yn-l-yl)-3- methyl-l-[(4-methyl quinazolin-2-yl)methyl] -3,7-dihydro-lH-purine-2,6-dione and pharmaceutically acceptable salts thereof used in preparing the compound may be obtained by methods described in the US Patent No. 7,407,955 which are herein incorporated by reference in their entirety.
The 8-[(3i?)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3- methyl-l-[(4-methyl quinazolin-2-yl)methyI] -3,7-dihydro-1H-purine-2,6-dione used as a starting material can be in any form, e.g. it can be a free base or a physiologically acceptable salt, in any polymorphic form or in a mixture of any polymorphic forms in a reaction solution, suspension, crude or in anhydrous, hydrated or solvated form.
In an embodiment-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3- methyl-l-[(4-methyl quinazolin-2-yl)methyl] -3,7-dihydro-lH-purine-2,6-dione with nateglinide in a solvent-free media, thus producing novel compound of 8-[(3i?)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3-methyl-l-[(4-methyl quinazolin-2-yl)methyl] -3,7-dihydro-1H-purine-2,6-dione with nateglinide free of solvents or having a negligible solvent content.
The nateglinide base used in preparing the Pharmaceutical Compounds may be obtained by methods described in the prior art which are herein incorporated by reference in their entirety. The nateglinide used as a compound former can be in any form, e.g. it can be in a reaction solution, suspension, crude or in anhydrous, hydrated or solvated form.
Just as a polymorph, solvate, hydrate or amorphous form of an API can modulate stability, solubility, and hygroscopicity, the Pharmaceutical Compounds prepared according to the present invention can modulate those same properties.
In another embodiment, the Pharmaceutical Compounds of the present invention are in a substantially pure form, preferably substantially free from other amorphous, crystalline and /or polymorphic forms. In this respect "substantially pure" relates to at least about 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of the pure compound. In this respect "substantially free from other amorphous, crystalline and /or polymorphic forms" means

not more than 20%, 15%, 10%, 5%, 4%, 3%, 2% or 1% of these other amorphous, crystalline and /or polymorphic forms are present in the form according to the invention.
These novel Pharmaceutical Compounds show higher solubilty, dissolution rates and also found to be stable under accelerated conditions. The changes in the properties of the active agent when prepared as a compound, are particularly advantages for the delivery of poorly soluble active agent in lower amounts.Thus, in yet another aspect, the invention provides synergistic pharmaceutical compositions comprsing novel Pharmaceutical Compound of (2R)-4-oxo-[3-(trifiuoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide and/ or 8-[(3i?)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3- methyl-l-[(4-methyl quinazolin-2-yl)methyl] -3,7-dihydro-lH-purine-2,6-dione with nateglinide together with one or more pharmaceutical carriers/excipients/ diluents.
The novel Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide and/ or 8-[(3R)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3- methyl-1-[(4-methyl quinazolin-2-yl)methyi] -3,7-dihydro-lH-purine-2,6-dione with nateglinide have been found to be effective for the release of insulin after blood sugar rises resulting in enhanced glucose-dependent insulin secretion from the pancreas and decreased hepatic glucose production. Pharmaceutical compositions according to the present invention comprise, novel Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide and/ or 8-[(3it)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3- methyl-l-[(4-methyl quinazolin-2-yl)methyl] -3,7-dihydro-lHpurine-2,6-dione with nateglinide as an active ingredient together with one or more pharmaceutically acceptable carriers, excipients or diluents. Any conventional technique may be used for the preparation of pharmaceutical compositions according to the invention.
The invention also concerns a medicament or pharmaceutical composition comprising novel Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yI]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide and/ or 8-[(3R)-3-ammopiperidm-l-yt]-7-(but-2-yn-l-yl)-3- methyl-1-

[(4-methyl quinazolin-2-yl)methyl] -3,7-dihydro-lH-purine-2,6-dione with nateglinide according to the inventions described above and optionally one or more pharmaceutically acceptable excipients for the treatment or prevention of Type 2 diabetes.
In a further embodiment, the present invention provides a method of treating Type 2 diabetes which method comprises administering 'an effective amount' of the composition of the invention comprising Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[I,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide and/ or 8-[(3.R)-3-aminopiperidin-l-y]]-7-(but-2-yn-l-yl)-3- methy 1-1 -[(4-methyl quinazolin-2-yl)methyl] -3,7-dihydro-lH-purine-2,6-dione with nateglinide to the subject sufferering from Type 2 diabetes.
The therapeutically effective dosage of any specific compound, the use of which is in the scope of present invention, will vary some what from compound to compound, and patient to patient, and will depend upon the condition of the patient and the route of delivery.
Preferably the invention provides a pharmaceutical composition containing
Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-
dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide and/ or 8-[(3R)-3-aminopiperidin-]-yl]-7-(but-2-yn-l-yi)-3- methyl-1-[(4-methyl quinazolin-2-yl)methyl] -3,7-dihydro-1H-purine-2,6-dione with nateglinide, in an amount of 0.01 to 99.5% in combination with a pharmaceutical ly acceptable carrier or diluent.
Suitably, the pharmaceutical composition comprising novel Pharmaceutical Compounds is in the form of a tablet suitable for oral delivery.
In another embodiment, the invention disclose use of the composition of the invention comprising Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide and/ or 8-[(3R)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3- methyl-1-

[(4-methyl quinazolin-2-yl)methyl] -3,7-dihydro-lH-purine-2,6-dione with nateglinide in preparing the medicament intended to treat or prevent Type 2 diabetes.
The association of the active principles in the same crystal exhibits several advantages especially if pharmaceutically formulated. They behave as a single chemical entity, thus facilitating the treatments, formulation, dosage etc.
In addition, the two active principles are complementing each other in the treatment especially, of Type 2 diabetes, but possible also of various other diseases or symptoms such as obesity, insulin resistance syndrome X. Thus, the Pharmaceutical Compounds according to the invention do exhibit a high number of advantages over the state of the art.
The present invention is illustrated below with the help of the following figures and examples.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for the purpose of illustrative discussion of preferred embodiments of the invention.
BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS:
Figure 1 is an X-ray powder diffractogram (XRD) of novel Pharmaceutical Compound of(2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide.
Figure 2 is a Differential Scanning Calorimetry (DSC) thermogram of novel
Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-
dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide.

Figure 3 is an Infra-Red (IR) absorption spectrum of novel Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]tria2olo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide.
Figure 4 is an X-ray powder diffractogram (XRD) of novel Pharmaceutical Compound of 8-[(3ii)-3-aminopiperidin-l -yl]-7-(but-2-yn-l-yl)-3- methyl-1 -[(4-methyl quinazolin-2-yl) methyl] -3,7-dihydro-lH-purine-2,6-dione with nateglinide.
Examples Example 1
A solution of (2R)'4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine phosphate (10 g, 0.01980 moles) in 50ml DI water was heated to 50°C. To the clear solution was added slowly, a solution of nateglinide (12.6g, 0.03968moles) in 60 ml acetone. The reaction mass was further stirred for 1.5-2 hrs at 50-55°C.The stirred solution was allowed to cool to room temperature. Stirring at room temperature was continued for about 3 hrs to allow crystallization to occur. The solids were collected by filtration and dried in vacuo at 45-50°C to yield 18.0 g of Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide. Efficiency:- 87%
Example 2
(2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine (10 g, 0.02457 moles) and nateglinide ( 15.4 6g, 0.04850moles) were combined with 100 ml acetonitrile and the mixture was heated to 80°C to effect dissolution. The stirred solution was allowed to cool to room temperature. Stirring at room temperature was continued for about 3-4 hrs to allow crystallization to occur. The solids were collected by filtration and dried in vacuo at 45-50°C to yield 22.0g of Pharmaceutical Compound of ( (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazoIo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluoro phenyl) butan-2-amine with nateglinide, Efficiency: - 86 %

Example 3
8-[(3R)-3-aminopiperidin-l -yl]-7-(but-2-yn-l -yl)-3- methyl-1 -[(4-methyl quinazolin-2-yl)methyl] -3,7-dihydro-lH-purine-2,6-dione (1.0 gm,0.00211moles ) and Nateglinide (0.67gm, ,0.00211 moles) were combined with 10 ml methanol and the mixture was stirred for 3 hour at 25-30°C. The solids were collected by filtration, washed with diisopropyl ether and dried in vacuo at 45-50°C to yield 1.35 g of Pharmaceutical Compound of 8-[(3R)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3-methyl-l-[(4-methylquinazolin-2-yl) methyl] -3,7-dihydro-lH-purine-2,6-dione with nateglinide. Efficiency:- 80.83%

WE CLAIM,
1. Pharmaceutical Compound comprising DPP-4 inhibitor and meglitinide.
2. Pharmaceutical Compound according to claim 1, wherein the DPP-4 inhibitor is selected from the group consisting of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro [l,2,4]triaolo[4,3-a]pyTazin-7(8H)-yl]-l -(2,4,5- trifluorophenyl)butan-2-amine ; (S)- 1 -[(3 -hydroxy- 1- adamantyl)amino]acetyl-2-cyano-pyrrolidine; (15',35,5,S)-2-[(2,S)-2-amino-2-(3-hydroxy-l-adamantyl) acetyl]-2-azabicyclo [3.1.0]hexane-3-carbonitrile; 8-[(3R)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3-methyl-l-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-lH-purine-2,6-dione; 2-({6-[(3i?)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-
1 (2H)-yl}methyl) benzonitrile; (2S,4S)-4-Fluoro-1 -[2-[[(lR,3S)-3-(l H-1,2,4-
triazoI-l-ylmethyl)cyclopentyl] amino]acetyl]-2-pyrrolidinecarbonitrile; (2S,4S)-
1 - [(2 S) -2 -ami n o-3,3 -bis(4 -fl uorophenyl) propanoy 1] -4-fl uoropyrro lidine-2 -
carbonitrile;l-[N-[3(R)-Pyrrolidinyl]glycyl]pyrrolidin-2(R)-ylboronic acid; and 1-{(2S)-2-amino-4-[2,4-bis (trifluoro methyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl] -4-oxobuty1} -5,5 -difluoropiperidin -2 -one.
3. Pharmaceutical Compound according to claim 1, wherein the meglitinide is selected from nateglinide and repaglinide.
4. Pharmaceutical Compound according to any one of claims 1 to 3, wherein the compound is in an amorphous form or a crystal form.
5. Pharmaceutical Compound as claimed in claim 4—is selected from a group
consisting of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triaolo[4,3-
a]pyrazin-7(8H)-yl]-l -(2,4,5- trifluoropheny 1) butan-2-amine with nateglinide;
(2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triaolo[4,3-a]pyrazin-7(8H)-yI]-
1-(2,4,5- trifluoro phenyl)butan-2-amine with repaglinide ;(S)- 1 -[(3 -hydroxy- 1-
adamanty])amino]acetyl-2-cyano-pyrrolidine with nateglinide,(S)- 1 -[(3 -
hydroxy- 1- adamantyl)amino]acetyl-2-cyano-pyrrolidine with
repaglinide,(l5,35,55)-2-[(251-2-amino-2-(3-hydroxy-l-adamantyl) acetyl]-2-

azabicyclo[3.L0]hexane-3-carbonitrile with nateglinide; (]S,3S,5S)-2-[(2S)-2-
amino-2-(3-hydroxy-1 -adamantyl) acetyl]-2-azabicyclo[3.1.0]hexane-3-
carbonitrile with repaglinide; 8-[(3R)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3-
methyl-l-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-lH-purine-2,6-dione
with nateglinide; 8-[(3R)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yI)-3- methyl-1-
[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-lH-purine-2,6-dione with
repaglinide ; 2-({6-[(3R)-3-aminopiperidin-1 -yl]-3-methyl-2,4-dioxo-3,4-
dihydropyrimidin-l(2H)-yl}methyl) benzonitrile with nateglinide; 2-({6-[(3R)-3-
aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl}methyl)
benzonitrile with repaglinide ; (2S,4S)- 4-FIuoro-l-[2-[[(1R,3S)-3-(lH-l,2,4-
triazol-l-ylmethyl)cyclopentyl]amino] acetyl]- 2-pyrrolidinecarbonitrile with
nateglinide; (2S,4S)-4-Fluoro-l-[2-[[(lR,3S)-3-(lH-l,2,4-triazol-l-
ylmethyl)cyclopentyl]amino]acetyl]-2-pyrrolidinecarbonitrile with repaglinide; (2S,4S)-l-[(2S)-2-amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrroIidine-2-carbonitrile with nateglinide; (2S,4S)-l-[(2S)-2-ammo-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitriIe with repaglinide; 1-[N-[3(R)-F7rrolidinyl]glycyl]pyrrolidin-2(R)-ylboronic acid with nateglinide; 1-[N-[3(R)-Pyrrolidinyl]glycyl]pyrrolidin-2(R)-ylboronic acid with repaglinide; 1-{(25)-2-amino-4-[2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-y 1] -4-oxobuty 1} - 5,5 -difluo rop iper idin-2-one w ith nateglin ide; 1 - {(2S)-2-
amino-4-[2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H-yl]-4-oxobutyl}-5,5-difluoropiperidin-2-one with repaglinide.
6. Pharmaceutical Compound according to claim 5, wherein the ratio between DPP-4 inhibitor and meglitinide is 1:1,1:1.5, 1.5:1,1:2 or 2:1.
7. Pharmaceutical Compound as claimed in claim 5, is (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triaolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine with nateglinide.
8. Pharmaceutical Compound according to claim 7; wherein the molecular ratio between (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triaolo[4,3-a]pyrazin-

7(8H)-yl]-l-(2,4,5-trifmorophenyl) butan-2-amine and nateglinide is 1:1 to 1:2, preferably is 1:2.
9. Pharmaceutical Compound according to any of claims 7 or 8, characterized by a X-ray powder diffraction pattern with peaks at 5.24, 6.78, 11.22, 15.92, 18.18 and 20.88 °26 ± 0.2°26 as shown in Fig. 1.
10. Pharmaceutical Compound according to any of claims 7 to 9, characterized by having a DSC spectrum exhibiting a significant endothermic peak at about 148°C as shown in Fig. 2.
11. Pharmaceutical Compound according to any of claims 7 to 10, characterized by an Infrared absorption spectrum with peaks at 3307 cm-1, 2928 cm-1, 1698 cm-1,1647 cm-1 1526 cm-1, 1444 cm-1, 1278 cm-1, 1214 cm-1, 1144 cm-1, 1015 cm-1, 934 cm-1 ', 843 cm-1, 759 cm-1, 698 cm-1, 668 cm-1 and 574cm-1.
12. Pharmaceutical Compound according to any of claims 7 to II characterized by having an IR spectrum as shown in Fig.3.
13. A process for preparing a Pharmaceutical Compound of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triaolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine with nateglinide comprising the steps of: forming a solution of (2R)-4-oxo-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triaolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-amine and nateglinide in a suitable solvent at an appropriate temperature; promoting crystal growth and collecting the crystals, preferably by filtration and drying at elevated temperature.
14. Pharmaceutical Compound as claimed in claim 5, is 8-[(3i?)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3- methyl-l-[(4-methylquinazolin-2-yl)methyl] -3,7-dihydro-1 H-purine-2,6-dione with nateglinide.

15. Pharmaceutical Compound according to claim 14; wherein the molecular ratio between 8-[(3R)-3-aminopiperidin-l-yl]-7-(but-2-yn-1-yl)-3- methyl-l-[(4-methyl quinazolin-2-yl)methyI] -3,7-dihydro-lH-purine-2,6-dione and nateglinide is 1:1.
16. Pharmaceutical Compound according to any of claims 14 or 15, characterized by a X-ray powder diffraction pattern as shown in Fig. 4.
17. A process for preparing a Pharmaceutical Compound of 8-[(3R)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3- methyl- l-[(4-methyI quinazolin-2-yl)methyl] -3,7-dihydro-lH-purine-2,6-dione with nateglinide comprising the steps of: forming a solution of 8-[(3H)-3-aminopiperidin-l-yl]-7-(but-2-yn-l-yl)-3- methyl-l-[(4-methyl quinazolin-2-yl)methyl] -3,7-dihydro-lH-purine-2,6-dione and nateglinide in a suitable solvent or a solvent mixture at an appropriate temperature; collecting the resulting solids, preferably by filtartion and drying at elevated temperature.