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BR-102018070913-B1 - β-Amino-N-acylhydrazone compounds and β-Amino-N-acylhydrazides, pharmaceutical compositions thereof and process for their production.

BR102018070913B1BR 102018070913 B1BR102018070913 B1BR 102018070913B1BR-102018070913-B1

Abstract

The present invention relates to pharmaceutically acceptable β-amino-N-acylhydrazines and/or β-amino-N-acylhydrazides and their salts that exhibit DPP4 enzyme inhibitory activity and anti-inflammatory and/or anti-cytokine activity, hypoglycemic pharmaceutical compositions comprising such compounds, and processes for their production. The present invention also provides a method of treating diseases related to type 2 diabetes mellitus and its chronic complications, due to the DPP4 inhibition property and/or the anti-inflammatory and/or anti-cytokine activity.

Inventors

  • Lidia Moreira Lima
  • Eliezer Jesus De Lacerda Barreiro
  • Roberto Takashi Sudo
  • Gisele Zapata Sudo
  • BRYELLE ECCARD DE OLIVEIRA ALVES
  • LUIS EDUARDO REINA GAMBA

Assignees

  • UNIVERSIDADE FEDERAL DO RIO DE JANEIRO

Dates

Publication Date
20260317
Application Date
20181010

Claims (11)

  1. 1. N-acylhydrazone compounds, characterized by being inhibitors of the enzyme dipeptidyl peptidase-4 (DPP4) and having the general formula (I): where:A is phenyl, naphthyl, substituted phenyl and heteroaryl, chosen from:3,4-difluorobenzyl, 3,4-dichlorobenzyl, 3,4-dimethoxybenzyl, 1H-imidazol-4-yl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl, 1H-benzo[d]imidazol-5-yl, 1H-1,2,3-triazol-4-yl, 2-methyl-1H-imidazol-4-yl, 4-(trifluoromethyl)benzyl. furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H- 1,2,3-triazol-4-yl, 2H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 4H-1,2,4-triazol-4-yl, 4H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-5-yl, 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, 2H-tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl, pyridazin-6-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-5-yl, pyrazin-6-yl, 1,3,5- triazin-2-yl, 1,3,5-triazin-4-yl, 1,3,5-triazin-6-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1H-indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1H-indol-8-yl, 1H-indazol-3-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 1H-indazol-8-yl, 1H-benzo[d]imidazol-1-yl, 1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-benzo[d]imidazol-7-yl, 1H-benzo[d]imidazol-8-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzofuran-8-yl, benzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl, benzo[b]thiophen-8-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin- 6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl; R1 and R2 independently correspond to H or CH3W corresponds to -(R)-NH2, -(S)-NH2 or -(R,S)-NH2Y corresponds to -NH- or -N= (E)X corresponds to -CH2- or -CH= (E)K corresponds to halogens, OCH3 and CH3,B corresponds to O or Sou and their pharmaceutically acceptable salts.
  2. 2. Compounds according to claim 1, characterized by the inhibition of dipeptidyl peptidase-4 and its isoenzymes.
  3. 3. Compounds according to claims 1 and 2, characterized in that they are selected from the group comprising: (R,S,E)-3-amino-N'-(3,4-dimethoxybenzylidene)-4-(2,4,5-trifluorophenyl)butanehydrazide (12, LASSBio-2123) (R,S,E)-3-amino-N'-(3,4-difluorobenzylidene)-4-(2,4,5-trifluorophenyl)butanehydrazide (13, LASSBio-2124) (R,S,E)-3-amino-N'-(3,4-dichlorobenzylidene)-4-(2,4,5-trifluorophenyl)butanehydrazide (14, LASSBio-2125)(R,S,E)-N'-((1H-imidazol-4-yl)methylene)-3-amino-4-(2,4,5-trifluorophenyl)butanehydrazide (15, LASSBio-2126)(R,S)-3-amino-N'-(3,4-difluorobenzyl)-4-(2,4,5-trifluorophenyl)butanehydrazide: LASSBio-2127 (16, LASSBio-2127)(S,E)-3-amino-N'-(3,4-difluorobenzylidene)-N-methyl-4-(2,4,5-trifluorophenyl)butanehydrazide (17, LASSBio-2128) and combinations thereof.
  4. 4. Pharmaceutical composition, characterized by comprising: a) N-acylhydrazone compounds and derivatives that are inhibitors of the enzyme dipeptidyl peptidase-4 (DPP4) and have general formula (I): where:A is phenyl, naphthyl, substituted phenyl and heteroaryl, chosen from:3,4-difluorobenzyl, 3,4-dichlorobenzyl, 3,4-dimethoxybenzyl, 1H-imidazol-4-yl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl, 1H-benzo[d]imidazol-5-yl, 1H-1,2,3-triazol-4-yl, 2-methyl-1H-imidazol-4-yl, 4-(trifluoromethyl)benzyl. furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 2H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 4H-1,2,4-triazol-4-yl, 4H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-5-yl, 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, 2H-tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl, pyridazin-6-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-5-yl, pyrazin-6-yl, 1,3,5- triazin-2-yl, 1,3,5-triazin-4-yl, 1,3,5-triazin-6-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1H-indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1H-indol-8-yl, 1H-indazol-3-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 1H-indazol-8-yl, 1H-benzo[d]imidazol-1-yl, 1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-benzo[d]imidazol-7-yl, 1H-benzo[d]imidazol-8-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzofuran-8-yl, benzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl, benzo[b]thiophen-8-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin- 6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl, quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl, quinoxalin-8-yl; -(R,S)-NH2Y corresponds to -NH- or -N= (E)X corresponds to -CH2- or -CH= (E)K corresponds to halogens, OCH3 and CH3,B corresponds to O or Sou their pharmaceutically acceptable salts.b) a pharmaceutically acceptable vehicle.
  5. 5. Composition according to claim 4, characterized by the inhibition of DPP4 and/or its isoenzymes.
  6. 6. Composition, according to claims 4 and 5, characterized by anti-diabetic activity.
  7. 7. Composition, according to any one of claims 4 to 6, characterized by anti-inflammatory and/or anti-TNF activity.
  8. 8. Composition, according to any one of claims 4 to 7, characterized by activity in the treatment of chronic complications of type II diabetes.
  9. 9. Composition according to any one of claims 4 to 8, characterized in that the compounds are selected from the group comprising: (R,S,E)-3-amino-N'-(3,4-dimethoxybenzylidene)-4-(2,4,5-trifluorophenyl)butanehydrazide (12, LASSBio-2123) (R,S,E)-3-amino-N'-(3,4-difluorobenzylidene)-4-(2,4,5-trifluorophenyl)butanehydrazide (13, LASSBio-2124) (R,S,E)-3-amino-N'-(3,4-dichlorobenzylidene)-4-(2,4,5-trifluorophenyl)butanehydrazide (14, LASSBio-2125)(R,S,E)-N'-((1H-imidazol-4-yl)methylene)-3-amino-4-(2,4,5-trifluorophenyl)butanehydrazide (15, LASSBio-2126)(R,S)-3-amino-N'-(3,4-difluorobenzyl)-4-(2,4,5-trifluorophenyl)butanehydrazide: LASSBio-2127 (16, LASSBio-2127)(S,E)-3-amino-N'-(3,4-difluorobenzylidene)-N-methyl-4-(2,4,5-trifluorophenyl)butanehydrazide (17, LASSBio-2128); and combinations thereof.
  10. 10. Production process of derivatives of general formula (I) characterized by comprising the steps of: a) formation of the meldrum adduct of formula (II): b) decarboxylation of the previous compound to produce the compound with formula (III): c) two-step reductive amination, first obtaining the enamine of formula (IV): subsequent reduction of the compound obtained in the previous step forming the compound with formula (V): d) hydrazinolysis of the compound obtained in the previous step forming the compound with formula (VI): e) condensation with aldehydes of general formula (VII) and/or f) reduction of the imine double bond and/or g) protection of the amine functional group with phthalic anhydride of the compound obtained in step c) (VI), subsequent N-methylation and final deprotection of the functional group, obtaining the compounds with general formula (I): where:A is phenyl, naphthyl, substituted phenyl and heteroaryl, chosen from:3,4-difluorobenzyl, 3,4-dichlorobenzyl, 3,4-dimethoxybenzyl, 1H-imidazol-4-yl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl, 1H-benzo[d]imidazol-5-yl, 1H-1,2,3-triazol-4-yl, 2-methyl-1H-imidazol-4-yl, 4-(trifluoromethyl)benzyl. furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H- 1,2,3-triazol-4-yl, 2H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 4H-1,2,4-triazol-4-yl, 4H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-5-yl, 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, 2H-tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-thiadiazol-3-yl, 1,2,5-thiadiazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl, pyridazin-6-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-5-yl, pyrazin-6-yl, 1,3,5- triazin-2-yl, 1,3,5-triazin-4-yl, 1,3,5-triazin-6-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1H-indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1H-indol-8-yl, 1H-indazol-3-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 1H-indazol-8-yl, 1H-benzo[d]imidazol-1-yl, 1H-benzo[d]imidazol-2-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-6-yl, 1H-benzo[d]imidazol-7-yl, 1H-benzo[d]imidazol-8-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, benzofuran-8-yl, benzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl, benzo[b]thiophen-8-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin- 6-yl, quinolin-7-yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl,quinoxalin-2-yl, quinoxalin-3-yl, quinoxalin-5-yl, quinoxalin-6-yl, quinoxalin-7-yl,quinoxalin-8-yl; R1 and R2 independently correspond to H or alkyl or aryl or substituted aryl, heteroaryl or substituted heteroaryl, heterocycle or substituted heterocycles. -(S)-NH2 or -(R,S)-NH2Y corresponds to -NH- or -N= (E)X corresponds to -CH2- or -CH= (E)K corresponds to halogens, OCH3 and CH3B corresponds to O or Sou their pharmaceutically acceptable salts.
  11. 11. Process, according to claim 10, characterized by additionally comprising steps of interconversion of functional groups and/or protection and deprotection of functional groups.

Description

FIELD OF THE INVENTION [001] The present invention relates to pharmaceutically acceptable β-amino-N-acylhydrazone and/or β-amino-N-acylhydrazide derivatives and their salts which exhibit DPP4 enzyme inhibitory activity and anti-inflammatory and/or anti-cytokine activity, hypoglycemic pharmaceutical compositions comprising such compounds, and processes for their production. The present invention further provides a method of treating diseases related to type 2 diabetes mellitus due to the DPP4 inhibitory property and/or the anti-inflammatory and/or anti-cytokine activity of the compounds presented. BACKGROUND OF THE INVENTION [002] Diabetes Mellitus (DM) is a chronic, non-communicable disease characterized by hyperglycemia resulting from a relative or absolute deficiency of insulin, which may result from defects in the secretion or action of this hormone, produced by pancreatic β cells. DM is classified into two well-defined types: type 1 diabetes mellitus (DM1), more common in children and young people, accounting for about 10% of all diabetic patients diagnosed worldwide, and type 2 diabetes mellitus (DM2) (Cruz, G.L., et al. Diabetes Res. Clin. Pract. 2013, 99(2), 85), found more frequently in adults, accounting for 90% of diabetic patients. [003] The etiology of T2DM is directly linked to factors such as poor diet, sedentary lifestyle and obesity. Additionally, it is characterized by increased plasma insulin, with insulin resistance and subsequent reduction and atrophy of pancreatic β cells (Lontchi-Yimagou, E., et al. Curr. Diab. Rep. 2013, 13, 435). [004] Type 2 diabetes mellitus (T2DM) is a global public health problem and is associated with an increased risk of premature development of various complications, including cardiovascular diseases. Among the distinct and varied chronic complications associated with T2DM, nephropathy and coronary artery disease contribute to an increase of up to 3 times in mortality from cardiovascular diseases when compared to patients without metabolic syndrome. Meanwhile, lower limb ulceration, resulting from peripheral vascular disease and neuropathy, is the leading cause of non-traumatic amputations worldwide (www.idf.org (last accessed 28/01/2018), Alam, U. et al. Handb Clin Neurol. 2014, 126, 211). The incidence of neuropathy in diabetic individuals is approximately 15% in patients with type 1 diabetes and 20% in individuals with T2DM. This chronic complication takes on particular importance when considering the 27% mortality rate over ten years among patients with diabetic neuropathy (Jiyin Zhou & Shiwen Zhou, Mol Neurobiol. 2014, 49(1), 536). [005] The development of T2DM begins with insulin resistance, and this state may precede a diagnosis by several years (Resnick, H.E., & B.V. Howard. Annu. Rev. Med. 2002, 53,245). The accumulation of lipids, oxidative stress, and pro-inflammatory cytokines cause activation of stress-sensitive kinases with consequent inhibition of insulin signaling (Bunner, A.E., et al. World J. Diabetes. 2014, 5(2), 146). Alterations in insulin concentration and functionality promote abnormalities in lipid metabolism, favoring macrovascular complications in diabetes (Pitocco, D. et al. Int. J. Mol. Sci. 2013, 14(11), 21525). [006] Insulin, at physiological concentrations, acts as a vasodilator and stimulates endothelial NO production. In the endothelium, activation of the PI3K pathway is able to regulate insulin-dependent NO production. The presence of insulin resistance determines a combined defect in glucose transport and endothelium-dependent vasodilation (Bahia, L. et al. Arq. Bras. Endocrinol. Metab. 2006, 50(2), 291). [007] In hyperglycemia, glucose in the cytosol is diverted to the polyol pathway, where the enzyme aldose reductase reduces glucose to sorbitol, using NADPH as a cofactor from the pentose phosphate pathway. This excessive consumption culminates in NADPH depletion and results in the generation of ROS (Reactive Oxygen Species). These ROS stimulate the oxidation of low-density lipoprotein (LDL) and ox-LDL, which are not recognized by the LDL receptor and are taken up by macrophages, leading to the formation of foam cells and atherosclerotic plaques, resulting in vascular disorders associated with diabetes (Bessueille, L. & Magne, D. Cell. Mol. Life. Sci. 2015, 72, 2475). [008] Excessive production of ROS causes hyperglycemia-induced damage through the activation of several mechanisms (Pitocco, D. et al. Int. J. Mol. Sci. 2013, 14(11), 21525), such as: 1) Increased AGEs (Advanced Glycation End Products) formation, resulting from non-enzymatic glycation of plasma proteins, leading to their deposition in the subendothelial layer and inducing endothelial dysfunction. In effect, AGEs can directly inactivate eNO, which prevents endothelium-dependent vasodilation. In turn, the receptor for AGE binding (RAGE) induces ROS production, which activates NF-κB, causing multiple pathological alterations in gene expression. 2) PKC, protein kin