Specification
PENICILLAMINE AND ITS DERIVATIVES ARE USED IN THE TREATMENT OF
COPPER TOXICITY AND NASH
FIELD OF THE INVENTION
The present invention relates to novel compounds of the general formula (I), having compounds to treat copper toxicity, NASH and Leigh Syndrome , their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts, their pharmaceutical compositions, and their Prodrugs thereof. The present invention more particularly provides novel compounds of the general formula (I) and general formula (II)
The present invention also provides a process for the preparation of the above said novel compounds of the general formula (I) and general formula (II), their derivatives, their analogs, their stereoisomer's, their polymorphs, their hydrates, their solvates, their pharmaceutically acceptable salts and compositions.
The novel compounds of the formula (I) and (II) of the present invention are useful for the treatment of copper toxicity and Liver related diseases, which is one of the leading causes of death in the present society.
Copper is found in all living organisms and is a crucial trace element in redox Chemistry, growth and development. Overload or deficiency of copper is associated with Wilson disease (WD) and Menkes disease (MD), which are of genetic origin. Non alcoholic steatohepatitis (NASH) is a liver inflammation caused by accumulation of fat in the liver. Many people have a buildup of fat in the liver, and for most people it causes no symptoms and no problems. But in some people, the fat causes inflammation of the liver and because of inflammation, the liver does not work as well as it should.
TECHNICAL FIELD
This disclosure generally relates to compound and their synthesis. More particularly, this disclosure relates to treating mammals with pharmaceutically acceptable amount of compounds, compositions, formulations and the Prodrugs of the compound.
BACKGROUND ART
Pencillamine is a 3-mercapto-D-valine, a disease modifying antirheumatic drug used as a chelating agent in the treatment of Wilson's disease. It is also used to reduce cystine excretion in cystinuria and to treat patients with severe, active rheumatoid arthritis unresponsive to conventional therapy. It is a white or practically white, crystalline powder, freely soluble in water, slightly soluble in alcohol and insoluble in ether, acetone, benzene .... Etc. Few drugs are already approved by the FDA and available in the market with brand names "Cuprimine" and "Depen"
Metal toxicity may occur due to essential metal overload or exposure to heavy metals from various sources. Most metals are capable of forming covalent bonds with carbon, resulting in metal-organic compounds. Metals and metal compounds interfere with functions of various organ systems like the central nervous system (CNS), the haematopoietic system, liver, kidneys, etc. (Flora etal.2010).
Metal accumulation has been responsible for many dysfunctions in liver diseases. Pathophysiologic mechanisms responsible for cerebral dysfunction and neuronal cell death in hepatocerebral disorders, such as Wilson's Disease, post-shunt myelopathy, hepatic encephalopathy, and acquired non-Wilsonian hepatocerebral degeneration are a major feature of hepatocerebral disorders. Morphologic changes to astrocytes (Alzheimer type II astrocytosis) include neurotoxic effects of metals such as copper, manganese, and iron. Management and treatment of hepatocerebral disorders include chelation therapy (Wilson's Disease) and liver transplantation among others.
Copper accumulation has been responsible for many dysfunctions in liver, kidney and eye diseases. Excess copper is actually deposited throughout the corneas in Wilson's disease. Renal tubular dysfunction, with consequent hypercalciuria and hyperphosphaturia may induce nephroclacinosis. As pharmacological management penicillamine and trietine are being used. There have been some long term effects for using these medication and that has been discussed in the prior art (Pfeiffer 2007). There is a need for a development of new copper chelator and an anticancer metallodrug with improved specificity and decreased toxic side effects.
SUMMARY OF DISCLOSURE
In one embodiment, a compound comprising of Formula 1 and 2 are disclosed.
Another embodiment, a pharmaceutical composition comprising of one or more compounds of formula land 2, an intermediate, a Prodrug, pharmaceutical acceptable salt of compound formula 1 with one or more of pharmaceutical^ acceptable carriers, and vehicles or diluents are disclosed. These compositions may be used in the treatment of diseases related to copper retention and its complications in hepatic diseases and/or disorders.
In another embodiment, the present disclosure relates to the compound and composition of formula 1, or pharmaceutical^ acceptable salts thereof,
Wherein, R 1 , R2 , and R 3 each independently represents hydrogen, thiol, alkyl, alkyl thiol, Triphenyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl,, ether, ester, heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl; substituted alkyl thiol, substituted aryl thiol and
R5 represents represents hydrogen, thiol, alkyl, alkyl thiol, Triphenyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl; substituted alkyl thiol, substituted aryl thiol and
X is represented by O, S or NH
Rl and R4 represents as a protection such as represented as follows.
R4 represents at least one of a residue of guanidine, a residue of hydrazine, an acid, a residue of pyruvic acid, a residue of oxaloacetic acid, a residue of tocopherol, a residue of ascorbic acid, a residue of thiamine, thioctic acid, a residue of thioctic acid, a residue of acetyl cysteine, a residue of alpha-keto glutaric acid, a residue of dimercaprol, a residue of an NO donor, a residue of glutathione, (RS)-2, 3-disulfanylpropan-l-ol, (R)-2- acetamido-3-sulfanylpropanoic acid, Ecosapentanoic acid, different amino acids and an analog of any one of the foregoing and in general represented by the following structures.
COMPOUND 1
wherein, n represents an integer from 0 to 8;
wherein R4 is R^(+)-thioctic acid, wherein n is an integer that equals between 0 to 4.
In another preferred embodiment, formula 1 may represent the following compound:
In one embodiment, R1, R2 and R3 represents, hydrogen, methyl, ethyl or thiol and R4 represents R-isomer of residue or analog or derivative or metabolite of thioctic acid.
COMPOUND 2
In another embodiment, R , R and R represents, hydrogen, methyl, ethyl or thiol and R represents (RS)-2, 3-disulfanylpropan-l-ol.
COMPOUND 3
In another embodiment, R1, R2 and R3 represents, hydrogen, methyl, ethyl or thiol and R represents (R)-2-acetamido-3-sulfanylpropanoic acid.
Furthermore, this disclosure provides an embodiment comprising a composition: a) R-(+)-lipoic acid or Thioctic acid
b) Zinc acetate (or) Triethylene tetramine; and
c) a compound of Formula 1
Wherein,
R 1 , R2 , and R 3 each independently represents hydrogen, thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl; and
R represents at least one of a residue of guanidine, a residue of hydrazine, an acid, a residue of pyruvic acid, a residue of oxaloacetic acid, a residue of tocopherol, a residue of ascorbic acid, a residue of thiamine, thioctic acid, a residue of thioctic acid, a residue of acetyl cysteine, a residue of alpha-keto glutaric acid, a residue of dimercaprol, a residue of an NO donor, a residue of glutathione and an analog of any one of the foregoing.
R5 represents represents hydrogen, thiol, alkyl, alkyl thiol, Triphenyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl; substituted alkyl thiol, substituted aryl thiol.
Furthermore, in another embodiment is disclosed as a pharmaceutically acceptable composition, a pharmaceutically acceptable salt for example, but not limited to, tartrate, esylate, mesylate, sulfate, hydrate and hydrochloride salt of formula 1 comprising: a) R-(+)-lipoic acid (or) Acetylcysteine (or) Dimercaprol;
b) Zinc acetate (or) Triethylene tetramine; and
c) a compound of Formula 1 NH2 Formula 1
Wherein, R 1 , R2 , and R 3 each independently represents hydrogen, thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl; and
R4 represents at least one of a residue of guanidine, a residue of hydrazine, an acid, a residue of pyruvic acid, a residue of oxaloacetic acid, a residue of tocopherol, a residue of ascorbic acid, a residue of thiamine, thioctic acid, a residue of thioctic acid, a residue of acetyl cysteine, a residue of alpha-keto glutaric acid, a residue of dimercaprol, a residue of an NO donor, a residue of
glutathione, (RS)-2, 3-disulfanylpropan-l-ol, (R)-2- acetamido-3-sulfanylpropanoic acid and an analog of any one of the foregoing and
R5 represents represents hydrogen, thiol, alkyl, alkyl thiol, Triphenyl thiol, acetyl thiol, disulfide, acyl, acylalkyl, alkenyl, alkylthioalkyl, alkynyl, alkoxyaryl, alkoxyalkyl, aryl, aralkyl, aryloxyalkyl, arylthioalkyl, cycloalkyl, ether, ester, heteroaryl, heterocyclyl, lower alkyl, sulfone, sulfoxide, or hydroxyalkyl; substituted alkyl thiol, substituted aiyl thiol.
In one embodiment the therapeutically effective amount may be rendered, but not limited to, as an injection. Other embodiments may include peroral, topical, transmucosal, inhalation, targeted delivery and sustained release formulations. The topical application may be an ophthalmic drug used as drops, targeted delivery may be injection to the organ and peroral may be syrup, tablet or capsule.
Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein. The kits may further comprise instructions for use in the treatment of diseases related to copper retention, hepatic disorders or its related complications.
Furthermore, herein is provided a kit comprising a first composition and a second composition, wherein a) the first composition is R-(+)-lipoic acid or
Acetylcysteine or Dimercaprol; b) the second composition is a combination of
Compound 1A and/or Compound 2 and/or Compound 3 and c) the third composition is triethylene tetramine (or) Zinc acetate or Ammonium tetrathiomolybdate:
DETAILED DESCRIPTION
In the present disclosure metal chelating compounds, compositions, formulations and their use are disclosed. The compounds comprise derivatives of formula 1.
Furthermore, the composition of varies compounds comprise of R- lipoic acid,
Dimercaprol, Zinc acetate, Ammonium tetrathiomolybdate or triethylene tetramine is combined with a pharmaceutically acceptable salt of the compounds derived from formula 1. In another embodiment, methods of making the formula 1 into different compounds are disclosed.
The compound may also comprise of tartrate, esylate, mesylate, sulfate salts and hydrate salt of formula 1. Herein the application also provides a kit comprising any of the pharmaceutical compositions disclosed herein. The kit may comprise instructions for use in the treatment of diseases associated to copper toxicity, hepatic disorders or related complications.
According to another feature of the present invention, there is provided a process as shown in the following scheme, for the preparation of compounds of the formula (I), wherein all the groups are as defined earlier.
General Synthetic Scheme:
In the compound 1(a), the thiol group was reacted with suitable protecting agents like acetyl, triphenyl, substituted benzyl in suitable solvent and a suitable base and forms compound 1(b). Again in the compound 1(b), acid group was reacted with suitable protecting agents like tert-butyl, tert-butyl dimethyl silane, Thesyl dimetyl silane, methyl, ethyl, allyl, vinyl, isobutyl in suitable solvent and suitable bases like triethylamine, diisopropylethylamine, potassium carbonate, sodiumhydroxide forms compound 1(c). In compound 1(c) both the thiol and amine groups were combinely protected with paraformaldehyde, 2,2-dimethoxy propane forms compound 1(d). 1-Chloroethylchloroformate was reacted with compound 1(d) in suitable solvent and suitable bases like triethylamine, diisopropylethylamine, potassium carbonate, sodiumhydroxide forms compound 1(e). This compound 1(e) was reacted with acids like Lipoic acid, Ecosapentanoic acid, amino acids, 3-AcetyM,3-thiazolidine-4-carboxylic acid (Folcisteine), (232-dimethyl-l,3-dithiolan-4-yl) Methanol in suitable solvents like THF, DMF, alcohol, DMSO and suitable base like triethylamine, diisopropylethylamine, potassium carbonate, sodiumhydroxide, sodiummethoxide, sodiumhydride forms compound 1(f). Under mild hydrolysis with dilute acids or within the body in acidic environment gave Compound 1. This compound under acidic hydrolysis in the stomach gave ^-Penicillamine" and "R-(+>Lipoic acid"
This concept was observed in the lab experiments and needs to confirm in vivo results. The compound of the general formula (I) is prepared by the following procedure: Compound 1:
Synthetic scheme of Compound 1:
Procedure:
To a stirred solution of D-penicillamine (5.0 g, 0.033 mole; 1.0 eq) in methanol (100 mL; LR grade) was added thionyl chloride ( 40 gm, 0.33 mole, 10 eq) at 0 °C over 30 min and the reaction mixture was stirred for 48 h at room temperature. On completion of the reaction (monitored by TLC), the reaction mixture evaporate under reduced pressure to get white sticky solid mass. The residue was triturated with diethyl ether (2 x 100 mL) and dried under vacuum to get 6,1 gm compound as a white solid.
Yield%:6.1g(91%) Stag -2: Synthesis:
Procedure:
To stag-1 material (2.2 g, 0.011 moles; 1.0 eq) in Ethanol (25 mL, llvol) was added paraformaldehyde (1.0 g, 0.011 moles, 1 eq) and the reaction mixture was stirred for overnight.
On completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure to get sticky solid mass. The residue was triturated with ethyl acetate (2 x 25 mL) and dried under vacuum to get 1.68 gm compound as a white solid.
Yield%:1.68g(72%)
Procedure:
To stag-2 material. (1.27g, 0.0060 moles; 1.0 eq) in THF (15 mL, -12 Vol) was added diisopropylethyl amine (2.32 g, 0.017 moles, 3 eq) and the reaction mixture was stirred for 15-20 min at room temperature, a-chloroethyl chloroformate (1.29 g, 0.009 moles, 1.5 eq) in THF (5 mL) was added to reaction mass and the mixture was heat at 50 °C for 5 hrs. Progress of reaction was monitored by TLC. On completion of the reaction, the reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2 x 50 mL) followed by brine wash (1 x 25 mL). Collective organic layer was dried over anhydrous Na2S04 and evaporate in vacuo to obtain 1.96 g of crude material, which was as such used for next step (considering the 100 % yield).
Analytical Data: 'H-NMR (CDC13): 8 1.42 (s, 3H, -CH3), 1.59 (s, 3H, -CH3), 1.80- L84(m, 3H, -CH3), 3.77 (s, 3H, -OCH3), 4.26^4.40 (m, 1H, -CH), 4.65-4.78 (m, 2H, 2 x -CH), 6.50-6.55 (m, 1H, -CH-C1).
Stag -4: Synthesis:
Procedure:
To a stirred solution of R-Lipoic acid (1.24g, 0.0060 moles; 1.0 eq) in DMF (15 mL) was charged K2C03 (2.07 g, 0.015 moles; 2.5 eq) and the mass was heat to 50 °C for 1 hrs. Stag-3 material (1.69g, 0.0060 moles; 1.0 eq) in DMF (10 mL) was added to reaction mass at room temperature. The mixture was further heated to 50 °C for 6 hrs and then stirred at room temperature for overnight. Progress of reaction was monitored by TLC. On completion of the reaction, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (2 x 50 mL). Collective organic layer was washed with brine solution (1 x 50 mL) and dried over anhydrous Na2S04. organic layer was evaporate under reduced pressure to obtain 3.2 g of crude material, which was purified over 100-200 mesh silica using 9% ethyl acetate in hexane to get oily mass.
Analytical Data:
^-NMR (CDCI3): 5 1.25-1.7Q (m, 15H), 1.88-1.95 (m, 1H), 2.29- 2.35(m, 2H), 2.42- 2.50(m, 1H), 3.08- 3.01 (m, 2H), 3.54- 3.59(m, 1H), 3.76 (s, 3H, -OCH3), 4.27- 4.38(m, 1H), 4.67-4.74(m, 2H), 6.78-6.82 (m, 1H, -CH-C1).
Compound 2:
Stag-1; Synthesis:
Procedure:
To a stirred solution of D-penicillamine (5.0 g, 0.033 mole; 1.0 eq) in ethanol (30 mL, 6 vol) & water (10 mL, 2 vol) mixture was added paraformaldehyde (2.41 gm, 0.026 mole, 0.9 eq) at room temperature and the reaction mixture was stirred for 18 h at room temperature. On completion of the reaction (monitored by TLC), the reaction mixture was filter and obtained solid was washed with fresh ethanol (20 mL). The solid mass was suck dried under vacuum to get 5.2 gm compound as a white solid.
Yield%: 5.2 g (96 %)
Analytical Data: ^-NMR (D20): 5 1.45 (s, 3H, -CH3), 1.69 (s, 3H, -CH3), 4.01 (s, 1H, -CHCOOH), 4.44 -4.46 (d, 1H, J=9.76 Hz), 4.51-4.53 (d, 1H, JM9.76 Hz).
Stag -2: Synthesis:
Procedure:
To stag-1 material (5.0 g, 0.025 moles; 1.0 eq) in isopropanol (30 mL, 6 vol) & water (20 mL, 4 vol) mixture was added Boc anhydride (7.19 g, 0.032 moles, 1.3 eq) and the reaction mixture was stirred for overnight. On completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure to get sticky solid mass. The residue was dissolved in ethyl acetate (100 mL) and washed with water (1 x 50 mL). Collective organic layer dried over sodium sulfate and evaporate under reduced pressure to get 5.2 gm compound as a solid.
Yield%:5.2g(64%)
Product as such used for next step.
Procedure:
To stag-2 material (6.5g, 0.0024 moles; 1.0 eq) in DCM (30 mL, 4.6 vol) was added 4-dimethyl amino pyridine (1.51 g, 0.012 moles, 0.5 eq) and allyl alcohol (1.73 g, 0.029 moles, 1.2 eq). Cool above mixture to 0 °C and EDC.HC1 (4.78 g, 0.024 moles, 1 eq) was added at once. Reaction mixture was stirred for overnight at room temperature. On completion of the reaction (monitored by TLC), mass was dilute with DCM (50 mL) and washed with water (1 x 50 mL) followed by brine solution wash (1 x 50 mL). Collective organic layer dried over sodium sulfate and evaporate under reduced pressure to get 6.5 gm compound as oil.
Yield%: 6.5 g (86 %)
Analytical Data: 'H-NMR (CDC13): 8 1.41 (s, 9H, -t-butyl), 1.47 (s, 3H, -CH3), 1.58 (s, 3H, -CH3), 4.20- 4.35 (s, 1H, -CHCOOH), 4.63 - 4.72 (m, 4H, -OCH2 & -S-CH2-N-), 5.23-5.28 (m, 1H, -olefinic CH2), 5.34-5.38 (m, 1H, -olefinic CH2), 5.88-5.96 (m, 1H, -olefinic CH).
Procedure:
To a stirred solution of stage 3 material (6.4 g, 0.0021 moles; 1.0 eq) in DCM (20mL) was charged trifluoroacetic acid (8.45 g, 0.074 moles; 3.5 eq) and the mass was stirred for 20 hrs at room temperature. Progress of reaction was monitored by TLC. On completion of the reaction, the reaction mixture was dilute with DCM (50 mL) and washed with water (50 mL) followed by aq. NaHCC>3 solution wash (50 mL). Organic layer was washed with brine solution (1 x 50 mL) and dried over anhydrous Na2S04. Evaporate organic layer under reduced pressure to obtain 4.3 g of crude material, which was purified over 100-200 mesh silica using 14% ethyl acetate in hexane to get 2.98 gm of oily material.
Yield%:2.98g(69%)
Analytical Data: *H-NMR (CDC13): 5 1.28 (s, 3H, -CH3), 1.67 (s, 3H, -CH3), 3.66 (s, 1H, -CHCOOH), 3.79 (bs, 1H, -NH), 4.26 - 4.28 (d, 1H, J= 9.76 Hz, -S-CH2-N-), 4.42 - 4.44 (d, 1H, J= 9.76 Hz, -S-CH2JM-), 4.67 - 4.70 (m, 2H, COO-CH2), 5.28-5.30 (m, 1H? -olefinic CH2), 5.35-5.39 (m, 1H, -olefinic CH2), 5.88-5.98 (m, 1H, -olefinic CH).
Procedure:
To stag-4 material (1.94 g, 0.0096 moles; 1.0 eq) in THF (25 mL, -12 vol) was added diisopropylethyl amine (2.50 g, 0.019 moles, 2 eq) and the reaction mixture was stirred for 15-20 min at room temperature, a-chloroethyl chloroformate (1.93 g, 0.013 moles, 1.4 eq) in THF (5 mL) was added to reaction mass and the mixture was stirred at RT for 5 hrs. Progress of reaction was monitored by TLC. On completion of the reaction, the reaction mixture was filtered and mother liquor was evaporate under reduced pressure to get 4.4 gm of the crude material, which was as such used for next step (considering the 100 % yield).
Analytical Data: 'H-NMR (CDC13): 5 1.43 (s, 3H, -CH3), 1.60 (s, 3H, -CH3), 1.71 - 1.84 (m, 3H, -CH3), 4.35 (m, 1H, -CHCOOH), 4.61 - 4.79 (m, 4H, -S-CH2-N- & COO-CH2), 5.25-5.29 (m, 1H, -olefinic CH2), 5.35-5.39 (m, 1H, -olefinic CH2), 5.86-5.97 (m, 1H, -olefinic CH), 6.48-6.55 (m, 1H, - CH-C1).
Procedure:
To a stirred solution of R-Lipoic acid (2.0 g, 0.0097 moles; 1.0 eq) in DMF (20 mL) was charged K2CO3 (3.32 g, 0.024 moles; 2.5 eq) and the mass was heat to 50 °C for 20 min. Stag-5 material (2.96 g, 0.0096 moles; 1.0 eq) in DMF (10 mL) was added to reaction mass at room temperature. The mixture was further heated to 50 °C for 9 hrs and then stirred at room temperature for 12 hrs. Progress of reaction was monitored by TLC. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). Collective organic layer was washed with brine solution (1 x 100 mL) and dried over anhydrous Na2SC>4. Organic layer was evaporate
under reduced pressure to obtain 6.2 g of crude material, which was purified over 100-200 mesh silica using 12 - 30 % ethyl acetate in hexane yielded 0.269 gm of the product.
Analytical Data: 'H-NMR (CDC13): 8 1.42 - 1.73 (15H, 3 x -CH3,3 x -CH2), 1.87 - 1.95 (m, 1H), 2.27- 2.37(m, 2H), 2.42- 2.50(m, 1H), 3.08- 3.21(m, 2H), 3.53- 3.57(m, 1H),4.28 - 4.40 (m, 1H, -CHCOOH), 4.58 - 4.75 (m, 4H, -S-CH2-N- & COO-CH2), 5.24-5.29 (m, 1H, -olefinic CH2), 5.34-5.41 (m, 1H, -olefinic CH2), 5.86-5.97 (m, 1H, -olefinic CH), 6.76-6.83 (m, 1H, -CH-C1).
Definitions:
As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.
The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Likewise, preferred
cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5,6 or 7 carbons in the ring structure.
The term "alkyl" as Used herein refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 - propyl (n-Pr, n- propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l -propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, - C(CH3)3), 1-pentyl (n-pentyl,-CH2CH2CH2CH2CH3), 2-pentyl (- CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (- C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3 -methyl- 1 -butyl (- CH2CH2CH(CH3)2), 2-methyl-l -butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2 CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2- pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3- methyl-3-peiityl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, 1-heptyl, 1-octyl, and the like.
The term "alkenyl" refers to linear or branched-chain monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a carbon- carbon, sp double bond, wherein the alkenyl radical includes radicals having "cis" and "trans" orientations, or alternatively, !tE" and "Z" orientations. Examples include, but are not limited to, ethylenyl or vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like. The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i.e., a carbon- carbon, sp triple bond. Examples include, but are not limited to, ethynyl (-C^CH), propynyl (propargyl, - CH2C
Documents
Application Documents
| # |
Name |
Date |
| 1 |
5035-CHE-2015-Other Patent Document-210915.pdf |
2015-10-15 |
| 1 |
CERTIFIED COPIES TRANSMISSION TO IB [16-10-2016(online)].pdf |
2016-10-16 |
| 2 |
5035-CHE-2015 FORM-28.pdf |
2016-09-06 |
| 2 |
5035-CHE-2015-FORM28-210915.pdf |
2015-10-15 |
| 3 |
5035-CHE-2015-Form 1-210915.pdf |
2015-10-15 |
| 3 |
5035-CHE-2015-Form 5-210915.pdf |
2015-10-15 |
| 4 |
5035-CHE-2015-Form 2(Title Page)-210915.pdf |
2015-10-15 |
| 4 |
5035-CHE-2015-Form 3-210915.pdf |
2015-10-15 |
| 5 |
5035-CHE-2015-Form 2(Title Page)-210915.pdf |
2015-10-15 |
| 5 |
5035-CHE-2015-Form 3-210915.pdf |
2015-10-15 |
| 6 |
5035-CHE-2015-Form 1-210915.pdf |
2015-10-15 |
| 6 |
5035-CHE-2015-Form 5-210915.pdf |
2015-10-15 |
| 7 |
5035-CHE-2015 FORM-28.pdf |
2016-09-06 |
| 7 |
5035-CHE-2015-FORM28-210915.pdf |
2015-10-15 |
| 8 |
5035-CHE-2015-Other Patent Document-210915.pdf |
2015-10-15 |
| 8 |
CERTIFIED COPIES TRANSMISSION TO IB [16-10-2016(online)].pdf |
2016-10-16 |