Afatinib

439081-18-2

850140-73-7 dimaleate

Tovok, BIBW2992, Tomtovok

Boehringer Ingelheim Int,

An irreversible EGFR/HER2 inhibitor

N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide

4 – [(3-chloro-4-fluorophenyl) amino] -6 – {[4 – (N, N-dimethylamino)-1-oxo-2-buten-1-yl] – amino} -7 – ((S )-tetrahydrofuran-3-yloxy)-quinazoline

(E)-4-Dimethylamino-but-2-enoic acid {4-(3-chloro-4-fluoro- phenylanimo)-7-[(S)-(tetrahydro-furan-3-yl) oxy]-quinazolin-6-yl} -amide

 4 – [(3_ chloro-4 – fluorophenyl) amino] -6 – {[4_ (N, N-dimethylamino)-buten-1-oxo-_2_ – yl] amino}-7 – ((S) – tetrahydrofuran-3 – yloxy) – quinazoline

EMA:Link, US FDA:link

The endorsement for Giotrif (afatinib) covers the drug’s use in the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have the epidermal growth factor receptor (EGFR) gene mutation, which is present in about 10 per cent of people with NSCLC.

It caps a good month for Boehringer, which won US approval for the drug under the brand name Gilotrif two weeks ago, adding to the company’s list of therapy areas, which so far include chronic obstructive pulmonary disease (COPD), anticoagulation, HIV, Parkinson’s disease and diabetes.

In the US, the drug is approved alongside a companion diagnostic to help determine if a patient’s lung cancer cells express the EGFR mutations, whereas the EMA recommendation just includes the requirement that Giotrif be initiated and supervised by a physician experienced in the use of anti-cancer therapies.

  http://www.pmlive.com/pharma_news/boehringers_first_cancer_drug_leads_ema_recommendations_493051

GILOTRIF tablets contain afatinib, a tyrosine kinase inhibitor which is a 4-anilinoquinazoline. Afatinib is presented as the dimaleate salt, with the chemical name 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-, (2Z)-2-butenedioate (1:2). Its structural formula is:

Afatinib dimaleate is a white to brownish yellow powder, water soluble and hygroscopic, with an empirical formula of C₃₂H₃₃ClFN₅O₁₁, and a molecular weight of 718.1 g/mol.

GILOTRIF tablets for oral administration are available in 40 mg, 30 mg, or 20 mg of afatinib (equivalent to 59.12 mg, 44.34 mg, or 29.56 mg afatinib dimaleate, respectively). The inactive ingredients of GILOTRIF are the following: Tablet Core: lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magnesium stearate. Coating: hypromellose, polyethylene glycol, titanium dioxide, talc, polysorbate 80, FD&C Blue No. 2 (40 mg and 30 mg tablets only).

Afatinib (BIBW2992) is an irreversible EGFR/Neu inhibitor with an IC₅₀ of 14 nM. Afatinib is a potent inhibitor of EGFR phosphorylation. Afatinib showed positive results in assays against a variety of human cancer cell lines, including A431, murine NIH-3T3 cells, and breast cancer cell line BT-474.

Afatinib^[2] (INN; trade name Gilotrif in the US and Giotrif in Europe, previously Tomtovok and Tovok^[3]) is a drug approved inmuch of the world (including the United States, Canada, the United Kingdom and Australia) for the treatment of metastatic non-small cell lung carcinoma (NSCLC), developed by Boehringer Ingelheim.^[4][5][6] It acts as an angiokinase inhibitor.

Quinazoline derivatives, such as afatinib, are described in WO2002050043. This document also describes certain favourable pharmacological properties of this compound. The dimaleate salt and its crystalline form are described in WO2005037824.

 It is known in the W002/50043, which describes the pharmacological properties has important compounds include in particular their pharmacological properties mediated by the tyrosine kinase inhibitory effect and the signal transmission through the skin growth factor receptor (EGF-R) signal transduction mediated inhibitory effect. Therefore, this type of compounds are useful in the treatment of diseases, in particular for the treatment of tumor diseases, lung and gastrointestinal and respiratory tract and gall bladder and bile duct disease.

 W002/50043 discloses a method for preparing a compound wherein the amino crotonic group (IV), such as 4_ [(3 – chloro-4 – fluorophenyl) amino] -6 – {[4 – (N, N-two methyl-amino)-oxo-2-1_ – buten-1 – yl] amino} -7 – ((S) – tetrahydrofuran-3 – yloxy) – quinazoline in the one-pot reaction from the corresponding aniline component (II), bromo crotonic acid (III), oxalyl chloride and a secondary amine prepared (see Figure 1).

 Figure 1:

 In the method, the yield was 50% at most. In addition, the implementation typically purified by column chromatography. Therefore Preparation of 4 – [(3_ chloro-4 – fluorophenyl) amino] -6 – {[4 – (N, N-dimethylamino)-l-oxo-2 – buten-1 – yl] amino} -7 – ((S) – tetrahydrofuran-3 – yloxy) – quinazoline of the method is not for large-scale industrial production. Moreover, the method is not drawback bromo crotonate purchased by a large number of commercial sources, and the corresponding bromo-methyl crotonate only be obtained in a purity of about 80%.These methods are used in this case is also 4 – [(3 – chloro-4 – fluorophenyl) amino] -6 – {[4 – (N, N-dimethylamino) -1 – oxo – butene-1 – yl] amino} -7 – (⑶ – tetrahydrofuran-3 – yloxy) – quinazoline industrialized production adversely affect the applicability.

 In the above-mentioned drawbacks of known production methods, the present invention is to provide a produce aminocrotonate aryl amides, in particular 4 – [(3 – chloro-4 – fluorophenyl) amino] -6 – {[4 – (N, N-dimethylamino)-buten-1-oxo-_2_ – yl] amino} -7 – ((S) – tetrahydrofuran-3 – yloxy) – quinazoline The method of the method can be easily obtained using high purity starting materials and does not require the use of any material technology. Thus, the new method should be applicable on an industrial scale synthesis grade and therefore suitable for commercial applications.

This task is according to the present invention for preparing 4 – [(3 – chloro-4 – fluorophenyl) amino] -6 – {[4 – (N, N-dimethylamino) -1 – oxo-2 – buten-1 – yl] amino} -7 – (⑶ – tetrahydrofuran-3 – yloxy) – quinazoline, and other amino crotonic method based compound. In addition to high yield industrially embodiment, the synthesis method according to the present invention also has a very good purity and less than 0.1 of the advantages of a low cis content.

 According to Figure 2, in the method according to the present invention, an aryl group corresponding amino compound (V) with two – (Ch-ware yl) _ phosphono acetic acid, preferably with diethyl phosphonoacetate, by After appropriate activation, in a suitable reaction solvent, preferably for the use of the active 1,1 – carbonyldiimidazole, 1,1 – carbonyldiimidazole – triazole or propane phosphonic acid anhydride, is preferred for the use of 1, 1 – carbonyl diimidazole. The solvent used may be, for example, tetrahydrofuran (THF), dimethylformamide (DMF) or ethyl acetate.

The amide may be connected through any possible approach for activation, i.e., for example, 1,1 _ carbonyldiimidazole, 1,1 – carbonyldiimidazole – triazole, DCC (N, N-dicyclohexyl carbodiimide ), EDC (N ‘_ (dimethylaminopropyl)-N-ethylcarbodiimide), TBTU (0 – (benzotriazol-1 – yl)-N, N, N’, N ‘ – pan tetramethyluronium tetrafluoroborate), thiazolidine-2 – thione, or through the use of thionyl chloride may be converted to the corresponding acyl chloride. If desired, activation may be used an organic base such as triethylamine or pyridine embodiment, and can additionally added DMAP (dimethylaminopyridine). Suitable solvents include DMF, THF, ethyl acetate, toluene, chlorinated hydrocarbons or mixtures thereof.

http://www.google.com/patents/CN1867564B?cl=en

Example 1

{[4 – (3 – chloro-4 – fluoro – phenylamino) -7 – (⑶ – tetrahydrofuran _3_-yloxy) – quinazoline _6_ yl carbamoyl] methyl}-_ _ Diethyl

A 3. 58kg of 1,1 _ carbonyldiimidazole (22.16 mol) was placed in 12.8 l of tetrahydrofuran, and at a temperature of 40 ° C was dissolved in it with 6.5 l of tetrahydrofuran, 4. 52kg (22. 16 mol) of diethyl phosphono acetic acid mixture. Temperature at 40 ° C the mixture was stirred for 30 minutes. The resulting solution was referred to as Solution A.

 A 6. 39kg (17. 05 moles) of N4-(3_ _4_ chloro fluoro – phenyl) _7_ (tetrahydrofuran _3_ yloxy) quinazoline-4, 6 – diamine Add 26 5 of tetrahydrofuran at 40 ° C and the solution A were mixed and stirred at a temperature 30 ° C for 2 hours.To the suspension was added 64 l tert-butyl methyl ether and, after cooling to 20 ° C, the precipitate was removed by centrifugation. Using 16 liters of tetrahydrofuran and 16 l of a mixture of tert-butyl methyl ether, washed, and then washed with 32 liters of water and dried at 50 ° C.

 Yield: 6. 58kg (69. 8%) of white crystals, the content = HPLC 99. IFl%

 Example 2

 (E) -4 – dimethylamino – D -2 – acid – [4 – (chloro-3_ _4_ fluoro – phenylamino) _7_ (⑶ – tetrahydrofuran-3 – yloxy) – quinoline yl-6 – yl] – amide

 A 5.6 l of 30% hydrochloric acid (53.17 mol) was added to 4.4 liters of water. Then the temperature is under 30 ° C was added dropwise over 20 minutes 4. 28kg 95% of (dimethylamino) _ acetaldehyde – diethyl acetal (26.59 mol).Temperature at 35 ° C the reaction solution was stirred for 8 hours was cooled to 5 ° C and kept under argon. This solution is called Solution B.

 A 4. 55kg (68. 06 mol) of potassium hydroxide dissolved in 23.5 liters of water and cooled to _5 ° C. This solution is called Solution C.

 A 5. 88kg (10. 63 mol) ((4_ (3_ _4_ chloro fluoro – phenylamino) _7_ (tetrahydrofuran _3_-yloxy) – quinazolin-6 – yl carbamoyl) – methyl)-phosphonic acid diethyl ester and 0.45kg _ lithium chloride (10.63 moles) was placed in 23.5 l of tetrahydrofuran and cooled to -7 ° C. Was added over 10 minutes a cold solution of C. Then _7 ° C temperature of the solution was added over 1 hour B. At _5 ° C temperature for 1 hour under stirring the reaction mixture was heated to 20 ° C and mixed with 15 liters of water. After cooling to; TC temperature, the suspension was suction filtered, the precipitate was washed with water and dried. Yield: 5.21kg The crude product, 100%, water content: 6.7%.

 Using Titanium Dioxide / methyl cyclohexane embodiment the crystallization of the crude product.

 Yield: 78%, purity: HPLC99. 4F1%, water content: 5.4%

Example 3

 (E) -4 – dimethylamino – D -2 – acid – (4 – (chloro-3_ _4_ fluoro – phenylamino) ~ 7 ~ ((S) – tetrahydrofuran-3 – yl oxy) – quinazolin-6 – yl) – amide dimaleate

 A 6. Okg (12. 35 mol) of (E_) _4_ _2_ dimethylamino acid _ D – (4_ (3_ _4_ chloro fluoro – phenylamino) -7 – ((S) – tetrahydrofuran-3 – yloxy) – quinazolin-6 – yl) – amide into 84 liters of ethanol and heated to 70 ° C, and dissolved in 36 l of ethanol and 2.94kg (25.31 moles) of maleic acid was mixed . At the beginning of crystallization, the first mixture was cooled to 20 ° C and stirred for 2 hours and then at 0 ° C temperature for 3 hours. Precipitate was suction filtered, washed with 19 l of ethanol at a temperature of 40 ° C in vacuo.

Yield: 8. Ilkg (91. 5%)

Melting point: 178 ° C

[0096] 1H-NMR (CD3OD): δ = 2. 47 + 2. 27 (m + m, 2H), 2. 96 (s, 6H), 4. 03 (m, 2Η), 4. 07 +3 . 92 (m + m, 2Η), 4. 18 +4. 03 (m + m, 2Η), 5. 32 (m, 1Η), 6. 26 (s, 4H), 6. 80 (m, 1H ), 6. 99 (m, 1H), 7 · 27 (s, 1Η), 7 · 30 (t, 1Η), 7 · 66 (m, 1Η), 7 · 96 (dd, 1Η), 8 · 62 (s, 1Η), 9 · 07 (s, 1Η) ppm

13

PATENT

Examples:

Example 1

{[4 – (3-chloro-4-fluoro-phenylamino) -7 – ((S)-tetrahydrofuran-3-yloxy)-quinazolin-6-ylcarbamoyl]-methyl)-phosphonic acid diethyl ester

3.58 kg 1 ,1-carbonyldiimidazole (22.16 mole) were placed in 12.8 liters of tetrahydrofuran at 40 ° C with 4.52 kg (22.16 mol) diethylphosphonoacetic acid, dissolved in 6.5 liters of tetrahydrofuran, . The mixture is stirred for 30 minutes at 40 ° C. The solution thus obtained is referred to as solution A.

6.39 kg (17.05 mol) of N ⁴ – (3-chloro-4-fluoro-phenyl) -7 – (tetrahydrofuran-3-yloxy) quinazolin-4,6-diamine in 26.5 liters of tetrahydrofuran and submitted to 40 ° C and mixed with the solution A and stirred at 30 ° C for 2 hours. To 64 liters of suspension of tert -. Added butyl methyl ether and, after cooling to 20 ° C., the precipitate is removed by centrifugation. It is dried with a mixture of 16 liters and 16 liters of tetrahydrofuran tert-butyl methyl ether and then washed with 32 liters of water at 50 ° C. Yield: 6.58 kg (69.8%) of white crystals Assay: HPLC 99.1 area% Example 2

(E)-4-dimethylamino-but-2-enoic acid [4 – (3-chloro-4-fluoro-phenylamino) -7 – ((S) – tetrahvdrofuran-3-yloxy)-quinazolin-6yl1 amide

5.6 liters to 4.4 liters of water are added 30% hydrochloric acid (53.17 mol). Then 4.28 kg 95% pure (dimethylamino) acetaldehyde diethyl acetal (26.59 mol) at 30 ° C was added dropwise over 20 minutes. The reaction solution is stirred for 8 hours at 35 ° C, cooled to 5 ° C and kept under argon. This solution is referred to as solution B.

4.55 kg (68.06 mol) of potassium hydroxide are dissolved in 23.5 liters of water and cooled to -5 ° C. This solution is called solution C..

5.88 kg (10.63 mol) of ((4 – (3-chloro-4-fluoro-phenylamino) -7 – (tetrahydrofuran-3-yloxy) – quinazolin-6-ylcarbamoyl)-methyl)-phosphonic acid diethyl ester, and 0.45 kg lithium chloride (10.63 mole) were placed in 23.5 liters of tetrahydrofuran and cooled to -7 ° C. The cold solution C is added within 10 minutes. The solution B is added at -7 ° C over 1 hour. After stirring for one hour at -5 ° C, the reaction mixture is heated to 20 ° C and mixed with 15 liters of water. After cooling to 3 ° C, the suspension is filtered with suction, the precipitate washed with water and dried. Yield: 5.21 kg raw 100% Water content: 6.7%

The crystallization of the raw product is butyl acetate / methylcyclohexane yield: 78% HPLC purity 99.4 area%, water content 5.4% Example 3

(E)-4-dimethylamino-but-2-enoic acid (4 – (3-chloro-4-fluoro-pheny hvdrofuran-3-yloxy)-quinazolin-6YL) amide dimaleate

6.0 kg (12.35 mol) of (E)-4-dimethylamino-but-2-enoic acid (4 – (3-chloro-4-fluoro-phenyl-amino) -7 – ((S)-tetrahydrofuran- 3-yloxy) quinazolin-6YL)-amide are in 84 liters

Submitted ethanol and heated to 70 ° C and a solution of 2.94 kg (25.31 mol) of maleic acid in 36 liters of ethanol added.Following the onset of crystallization is first cooled to 20 ° C. and stirred for 2 hours, then 3 hours at 0 ° C. The precipitate is filtered off, washed with 19 liters of ethanol and dried in vacuum at 40 ° C.

Yield: 8.11 kg (91, 5%)

Mp: 178 ° C.

¹ H NMR (CD ₃ OD): δ = 2.47 + 2.27 (m + m, 2H), 2.96 (s, 6H), 4.03 (m, 2H), 4.07 + 3 , 92

(M + m, 2H), 4.18 + 4.03 (m + m, 2H), 5.32 (m, 1 H), 6.26 (s, 4H), 6.80 (m, 1 H ), 6.99 (m, 1 H), 7.27 (s, 1 H), 7.30 (t, 1 H), 7.66 (m, 1 H), 7.96 (dd, 1 H ), 8.62 (s, 1 H), 9.07 (s, 1H) ppm

…………..

U.S. Patent No. : 8,426,586  patent expires : October 10, 2029

WO200250043A1 (compound);

WO2003094921A2 (anticancer purposes);

WO2003066060A2 (anti-inflammatory purposes);

US2005085495A1 (process);

WO2005037824A2 (process);

WO2007085638A1 (process);

US2011207932A1 (process);

WO2011084796A2 (deuterated);

WO2012121764A1 (crystalline);

WO2013052157A1 (crystalline)

Chinese patents : CN1867564 

CN101402631 

UPDATE…………………

(WO2015186065) PROCESS FOR THE PREPARATION OF 4-DIMETHYLAMINOCROTONIC ACID

SUN PHARMACEUTICAL INDUSTRIES LIMITED [IN/IN]; Sun House, Plot No. 201 B/1 Western Express Highway Goregaon (E) Mumbai, Maharashtra 400 063 (IN)

VERMA, Shyam Sunder; (IN).
SINGH, Shravan Kumar; (IN).
SINGH, Kaptan; (IN).
PRASAD, Mohan; (IN)

Afatinib is a tyrosine kinase inhibitor disclosed in U.S. Patent Nos. RE43,431 and

6,251,912. Afatinib is depicted by Formula la:

Formula la

Afatinib is presented as the dimaleate salt and is chemically designated as 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(35)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2£)-,(2Z)-2-butenedioate (1 :2) having the structure depicted by Formula I:

Formula I

Processes for the preparation of 4-dimethylaminocrotonic acid or its salts are disclosed in U.S. Patent No. 7,126,025 and U.S. Publication No. 2012/0046494.

U.S. Patent No. 7,126,025 discloses a process for the preparation of 4-dimethylaminocrotonic acid or its salts by reacting but-2-enoic acid with

chlorotrimethylsilane in pyridine to obtain trimethylsilylcrotonate, which is brominated with a brominating agent under free radical conditions and in the presence of methylene chloride, acetonitrile, 1,2-dichloroethane, carbon tetrachloride, or ethyl acetate to give trimethylsilyl-4-bromocrotonate. The bromocrotonate compound is treated with dimethylamine in tetrahydrofuran to provide the 4-dimethylaminocrotonic acid.

U.S. Patent No. 7,126,025 also discloses a process for the preparation of 4-dimethylaminocrotonic acid by treating methyl or ethyl 4-bromocrotonate with dimethylamine to provide methyl or ethyl 4-dimethylaminocrotonate, which is hydrolyzed to provide the 4-dimethylaminocrotonic acid.

U.S. Publication No. 2012/0046494 discloses a process for the preparation of 4-dimethylaminocrotonic acid or its salts by converting alkyl 4-chloro-3 -hydroxy butyrate to alkyl 4-hydroxy crotonate, which is brominated to obtain alkyl 4-bromo crotonate. The alkyl 4-bromo crotonate is treated with dimethyl amine to provide alkyl 4-dimethylaminocrotonate, which is hydrolyzed to get the 4-dimethylaminocrotonic acid.

The use of pyridine or carbon tetrachloride is toxic to humans and therefore their use for the manufacture of a drug substance is not advisable. The bromocrotonate compounds, being lachrymatory in nature, are difficult to handle on an industrial scale.

The present invention provides a faster, more efficient, and industrially feasible process for the preparation of 4-dimethylaminocrotonic acid of Formula II, which is used as an intermediate for the preparation of afatinib or its salts.

A first aspect of the present invention provides a process for the preparation of 4-dimethylaminocrotonic acid of Formula II or its salts,

Formula II

comprising the steps of:

i) converting 2,2-diethoxy-N,N-dimethylethanamine of Formula III

Formula III

to ethyl-4-(dimethylamino)crotonate of Formula IV; and

Formula IV

ii) hydrolyzing the ethyl-4-(dimethylamino)crotonate of Formula IV.

A second aspect of the present invention provides a process for the preparation of afatinib of Formula la or its salts,

Formula la

comprising the steps of:

i) converting 2,2-diethoxy-N,N-dimethylethanamine of Formula III

Formula III

to ethyl-4-(dimethylamino)crotonate of Formula IV;

Formula IV

ii) hydrolyzing the ethyl -4-(dimethylamino)crotonate of Formula IV to obtain 4- dimethylaminocrotonic acid of Formula II or its salts; and

Formula II

iii) converting the 4-dimethylaminocrotonic acid of Formula II or its salts to afatinib of Formula la or its salts.

EXAMPLES

Example 1 : Preparation of ethyl-4-(dimethylamino)crotonate (Formula IV)

In a round bottom flask, 2,2-diethoxy-N,N-dimethylethanamine (Formula III, 200 g) and deionized water (100 mL) were added at about 20°C to about 25°C. To the solution, concentrated hydrochloric acid (240 mL) was added at about 25°C to about 50°C. The temperature of the reaction mixture was raised to about 70°C. The reaction mixture was stirred at about 60°C to about 70°C for about 12 hours. The reaction mixture was cooled to about 0°C. To the reaction mixture, about 200 mL of aqueous potassium hydroxide (240 g in 250 mL water) was added at about 0°C to about 10°C to attain a pH of 9.0. To the reaction mixture, ethyl(diethoxyphosphoryl) acetate (200 g) and 2-methyltetrahydrofuran (600 mL) were added at about 0°C to about 5°C. Further, 50 mL of aqueous potassium hydroxide was added to the reaction mixture at about -5°C to about 0°C to attain a pH of about 13.5. The reaction mixture was stirred at about -5°C to about 0°C for about 1 hour. The reaction mixture was filtered, and then the filtrate was recovered under vacuum at about 45°C to about 50°C to obtain ethyl-4-(dimethylamino)crotonate as an oily mass.

Yield: 89%

Example 2: Preparation of 4-dimethylaminocrotonic acid hydrochloride (Formula ID

In a round bottom flask, ethyl -4-(dimethylamino)crotonate (Formula IV, 120 g) and ethanol (480 mL) were added at about 25°C to about 35°C. To the solution, aqueous sodium hydroxide (30.5 g in 60 mL water) was added at about 10°C to about 20°C. The temperature of the reaction mixture was raised to about 50°C. The reaction mixture was stirred at about 50°C to about 55°C for about 1 hour. The reaction mixture was cooled to about 5°C. To the reaction mixture, concentrated hydrochloric acid (120 mL) was added to attain a pH of 1.5. The reaction mixture was filtered on Celite^® and washed with ethanol (50 mL). The filtrate was recovered under vacuum at about 55°C to about 60°C to obtain a crude mass. Ethanol (240 mL) was added to the crude mass, and then the reaction mixture was stirred at about 55°C to about 60°C for about 15 minutes to obtain a solution. In the solution, sodium chloride was obtained as a byproduct. The solution was filtered to discard sodium chloride. The filtrate was recovered under vacuum at about 55°C to about 60°C to obtain a residue. To the residue, isopropanol (400 mL) was added, and then the reaction mixture was stirred at about 55°C to about 60°C to obtain a clear solution. The solution was gradually cooled to about 25°C to about 30°C. The solution was further stirred at the same temperature for about 2 hours. The solid obtained was filtered, and then washed with isopropanol (50 mL). The solid was dried under vacuum at about 55°C to about 60°C to provide 4-dimethylaminocrotonic acid hydrochloride.

Yield: 63%

//////

Afatinib