FORM - 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION
"NOVEL PROCESS FOR SELECTIVE ISOLATION AND PURIFICATION OF 2-[4-(4-CHLOROPHENYL) CYCLOHEXYL]-3-CHLORO-l, 4-NAPHTHOQUINONE
AND ATOVAQUONE"
DISHMAN PHARMACEUTICALS & CHEMICALS LIMITED
A Company Incorporated Under The Indian Companies Act
Bhadr-Raj Chambers, Swastik Cross Roads,
Navrangpura, Ahmedabad-380 009,
Gujarat State, India
The following specification particularly describes the invention:

FIELD OF INVENTION:
The present invention relates to the improved method for preparation and
purification Atovaquone and its intermediate product. The present invention in
particular relates to an improved method for preparation and purification of the
intermediate trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l,4-
naphthoquinone (II) of formula - II and also preparation of stable form of 2-[trans-4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone (I) Atovaquone of formula - I and selective purification of the trans-2-[4-(4-chloropheny1)cyclohexyl]-3-chloro-l,4-naphthoquinone(II) with better yield and quality .

BACKGROUND OF INVENTION:
A wide range of studies of quiones derivatives like anthraquinones, naphoquinones and benzoquinones have been received considerable attention in medicinal chemistry. Such compounds have been variously described as having antimalarial, anticocidial and antotheilirial activities.
2-substituted-3-[4-(4-chlorophenyl)cyclohexyl]-1,4-naphthoquinone, which are described in US 5053432 is said to be active against the human malaria parasite Plasmodium falciparum also against Eimeria species such as E. tenella and E. acervulinam, which are causative organisms of coccidiosis. 2-substituted-3-[4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone has been described in literature as a compound possessing potent anti-malarial activity. Fieser and coworkers also disclosed the antimalarial activity of such compounds. 2-chloro-l,4-naphthoquinone(IV) was used as a starting material for preparation of all these compounds.

Atovaquone is the trans isomer of 2-chloro-3-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l-4-naphthoquinone(l), US 5053432 also disclose the synthetic routs for atovaquone . The process discloses in the said prior art is the reaction of 2-chloro-1,4-naphthoquinone (IV) with trans-4-(4-chlorophenyl)cyclohexane-l-carboxylic acid(III) in the solvent acetonitrile ,sulfolane and water in presence of silver nitrate, ammonium persulphate , which produces the mixture of cis and trans isomer of 2-[4-{4-chlorophenyl)cyclohexyl]-3-chloro-l,4-naphthoquinone(II) which is further proceeded to atovaquone in methanol and water and in presence of KOH as a base .
US 4,981,874 discloses the detailed process and synthesis along with the
activities and uses of Atovaquone, which is the trans isomer of 2-substituted-3-
[4-(4-chlorophenyl) cyclohexyl]-1,4-naphthoquinone. The essentially of the
process reported in the said prior art is the reaction of 2-chloro-1,4-
naphthoquinone(IV) with trans-4-(4-chlorophenyl)cyclohexane-l-carboxylic
acid(III) in the solvent acetonitrile in presence of silver nitrate, ammonium persulphate as per scheme-I

The residual sticky solid material after reflux and filtration is being extracted with boiled chloroform. A crude mixture cis and trans chloro intermediate (II) is obtained after evaporation of chloroform. The crude mixture is crystallized in acetonitrile yielding about 7% of chloro intermediate (II) which is due to formation

of the undesired cis isomer during reaction and which farther goes to mother liquor during crystallization. The overall yield upto final product Atovaquone is about 4-5 %.
The main drawback of the prior art is the poor yield of the intermediate, the analytical clarity for the exact ratio of Cis and trans isomer is not elaborated. The pure trans form of chloro intermediate is gained after a long workup which look non physible operations like extraction with boiling chloroform.
Tetrahedron Letters, Vol. 39, 7629-7632 Disclose the preparation of mixture of cis /trans chloro intermediate (with 1.3:1 ratio ) by reacting 2-chloro-1,4-naphthoquinone(IV) and trans-4-(4-chlorophenyl)cyclohexane-1-carboxylic acid(III) in acetonitrile, dichloromethane in presence of ammonium persulfate and catalytic silver nitrate. The crude intermediate is isolated and purified by flash chromatography using ethyl acetate/hexane to isolate about 10-14% of chloro intermediate.
The disadvantage of above process is the use of column chromatography for purification of crude chloro intermediate. This is the time and solvent consuming process and also not prefer for the commercialization of the process at large scale. Another drawback is about no clarity about the content of cis and trans ratio from the purification of Chloro intermediate and Atovaquone.
WO2008/122988 shows the purification in THF, direct isolation of atovaquone and conversion of cis into trans form in presence of xylene.
The drawback of this whole information that there is no information on the analysis of source as the whole information are link to the purification and conversion studies where source analysis is most important to see the real impact of the process.
Another drawback of process is the use of THF by dissolving and distillation of solvent. The use of THF is a risky during distillation due to its peroxide formation property as well as the price of commercial solvent also very high to compete with the market for commercial production

WO/2010/023686 Discloses the preparation of chloro intermediate by using 2-chloro-l,4-naphthoquinone(IV) and trans-4-(4-chlorophenyI)cyclohexane-1-carboxylic acid(III) in presence of silver nitrate and sodium persulfate with the relative batch volume against trans-4-(4-chlorophenyl)cyclohexane-l-carboxylic acid(III) with ratio of 20:20:5 for the reaction and 5 for sodium persulfate solution. After reaction completion, cis and trans chloro intermediate is extracted by 12 Volume of toluene, the resulting organic layer is washed with (lOVolume x 2) of sodium chloride solution After distill out toluene under vacuum, 12Volume of acetonitrile is used to isolate the crude product which is further purify by using 5Volume of dichloromethane and 9.5Volume of methanol to yield with 0.34 w/w of chloro intermediate.
The drawback of the above process is the use of very high volume of all the solvents and water which results to the higher effluent and negative effect to cost, less productivity due to higher time cycle and operations. The process is therefore non ecofriendly and less productive.
Many other references are reported involving the studies on polymorphism and different forms.
US 2006/0241311A1 discloses three different polymorphic forms of Atovaquone designates as Form I, Form II and Form III and also provides the analytical data for those forms. In this publication, basic product patent US patent no. 4981874 was characterized and designated as Form I.
This shows the characteristic peaks in XRD at about 7.2, 11.04, 11.77, 19.34, 21.14, 24.61, 25.28 and 28.4 ±0.2 degrees and DSC thermogram of Form I having small endotherm at 197°C, followed by a sharp endotherm at 222°C
Another form shows the characteristic peaks in XRD at about 7.02, 9.68, 10.68, 11.70, 14.25, 14.83, 18.60, 19.29, 23.32 and 24.54 ±0.2 degrees and DSC thermogram of Form II having small endotherm at 169°C, followed by a sharp endotherm at 222°C.

One more form shows the characteristic peaks in XRD at about 6.99, 9.65, 12.67, 20.07, 20.65, 20.99, 21.88, 22.10 and 22.56 ±0.2 degrees and DSC thermogram of Form III having a sharp endotherm at 222°C.
WO 2009/001367 A2 discloses Atovaquone crystalline Form A and Form B and process of preparation thereof. Atovaquone Form A characterized by X-ray powder diffraction pattern peaks at about 7.3, 10.0, 14.4, 15.1, 18.8, 20.4, 22.2, 23.6 and 24.6±0.2 degrees and DSC thermogram having a sharp endotherm at 221°C. Atovaquone Form B characterized by X-ray powder diffraction pattern peaks at about 9.7, 18.6, 19.3, 19.9, 20.1, 20.5, 22.2, 22.8, 23.3, 24.4, 24.6, 26.4, 26.9 and 28.8±0.2 degrees and DSC thermogram having small endotherm in range 150 to 160°C, followed by a sharp endotherm in range 222°C to 224°C.
US 2009/0221715 Al reported the novel polymorph of Atovaquone Form IPCA-ATO. Atovaquone Form IPCA-ATO characterized by X-ray powder diffraction pattern peaks at about 6.6, 10.05, 13.11, 18.27 and 23.10 ±0.2 degrees and DSC thermogram having small endotherm in range 117 to 130°C, followed by a sharp endotherm in range 220°C to 222°C.
US 2009/0105350 Al discloses the process for preparation of Atovaquone shows the character stick peaks at about 7.0, 9.7, 14.2, 14.8,17.0, 19.2,20.4,22.1 ,22.7,26.9 and 28.7 and further comparing and matching with USP std (Lot No. FOB190), which is disclose as Form III in US 2006/0241311.
OBJECTS OF THE PRESENT INVENTION:
• The objective of the invention is the selective isolation of 2-[4-(4-chlorophenyl) cyclohexyl]-3-chloro-l,4-naphthoquinone(II).
• Another object of the present invention to develop a plant viable and cost effective process of 2-[4-(4-chlorophenyI) cyclohexyIj-3-chloro-l,4-naphthoquinone(II) by minimizing the reaction volumes to reduce the process time and increase the productivity.

• The other object of the present invention is to employ a selective solvent/water combinations for isolating 2-[4-(4-chlorophenyl) cyclohexyl] -3-chloro-l, 4-naphthoquinone (II).
• The other object of the present invention is to employ a purification of the compound of 2-{4-(4-chlorophenyl) cyclohexyl]-3-chloro-l, 4-naphthoquinone (II) employing with solvent like cyclohexane, dichloromethane, methanol, toluene and ethyl acetate.
• Still another object of the present invention is selective purification of the compound atovaquone (I) employing with solvent like acetone, acetonitrile, ethyl acetate, methanol and isopropyl alcohol for better purity and selectivity,
• Preferred object of the present invention is to obtain atovaquone of formula - I with high purity and selectivity over the prior art with the characteristic peaks at different PXRD and DSC matching to the USP reference standard (Lot No. FOB190).
SUMMARY OF THE INVENTION:
The present invention provides a novel method for selective isolation for intermediate of 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l,4-naphthoquinone of formula - II as depicted above and its use thereof for preparation of atovaquone of formula (I). The essential process steps desired for operation of the invention including purification is given below:
• Reaction of 2-chloro-l,4-naphthoquinone(IV) with trans-4-(4-
chlorophenyl)cyclohexane-1- carboxylic acid (III) in acetonitrile, sulfolane
and water with the equal ratio of these solvents with the relative volume
ranging from 1 to 10 in presence of silver nitrate by using as an oxidant of
sodium persufate, ammonium persulfate, to give the intermediate of 2-[4-
(4-chlorophenyl)cyclohexyl]-3-chloro-l,4-naphthoquinone compound of
formula (II) which is purified by the selected solvent mixture/single from
ethyl acetate, cyclohexane, dichloromethane, methanol.


• Treating the compound of formula (II) with a base in alcoholic solvent, to afford the crude atovaquone of formula (I), organic impurities removed by extraction by organic solvents like MDC, cyclohexane, ethyl acetate and toluene at basic pH which is further purified with isopropyl alcohol, acetone and acetonitrile.

DELAILED DESCRIPTION OF THE INVENTION:
The present invention provides a process for preparation and purification of atovaquone of formula (I) and its intermediate of formula (II). The process of the invention is illustrated in scheme-II and is described below.
Accordingly, the invention provides an improved, scalable and efficient manufacturing procedure for preparation and purification of 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l,4-naphthoquinone(II) and Atovaquone (I).
The process for preparation of the intermediate 2-[4-(4-chlorophenyl) cyclohexyl]-3-chloro-l,4-naphthoquinone(II) comprising the steps of :
(1) Reacting trans-4-(4-chlorophenyl)cyclohexane-l-carboxylic acid(III) and 2-chloro-l,4-naphthoquinone (IV) in presence of silver nitrate, ammonium persulfate in a suitable organic solvent sulfolane, acetonitrile or preferably combination thereof;
(2) Isolation of intermediate by adding organic solvents;
(3) Purifying the intermediate.


According to the present invention, The process for preparation of the intermediate 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-1,4-naphthoquinone(II) reacting trans-4-(4-chlorophenyl)cyclohexane-l-carboxylic acid(III) and 2-chloro-1,4-naphthoquinone (IV) in presence of silver nitrate and ammonium persulfate in a suitable organic solvent aqueous combination. The solvents used are sulfolane, acetonitrile with water with combination is the equal ratio ranging volume of 1 to 10 but preferably 1 to 5.
According to the present invention, suitable organic solvent used in the said reaction for precipitation may be a linear, cyclic hydrocarbon such as hexane, heptane, cyclohexane, toluene, xylene etc. and polar solvents like dichloromethane, ethyl acetate , methanol or combination thereof. The most preferred solvent which is selected for isolation of the intermediate is a combination of ethyl acetate and cyclohexane wherein ratio of solvent ethyl acetate and cyclohexane (1:10) and (10:1) with respect to starting material trans-4-(4-chlorophenyl)cyclohexane-l-carboxylic acid (III) is used, most preferably ratio of ethyl acetate to cyclohexane is 1:1 to 5 .
The invention provides the process for selective isolation of the intermediate without removing the reaction solvent from reaction mass.
The invention further provides the process wherein the isolation by filtration is carried out at any temperature in the range of 20-60°C, preferably 25-35°C.
The present invention also provides the process wherein the suitable organic solvent for dissolving the compound to remove the inorganic salt, may be

toluene, ethyl acetate, dichloromethane, chloroform etc, or a combination thereof and most preferably dichloromethane.
The present invention is to provide a purification employing with solvent like cyclohexane, dichloromethane, methanol, toluene and ethyl acetate preferably ethyl acetate, dichloromethane and toluene.
The process for preparation of atovaquone of scheme-Ill comprising the steps of:
(1) Hydrolysis of 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l,4-naphthoquinone(II);
(2) Washing the reaction mass with organic solvent;
(3) Adjust the acidic pH;
(4) purified with organic solvent and
(5) Preparation of stable Form of atovaquone as per pharmacopeal standards.

According to the present invention , the process for Hydrolysis of 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l,4-naphthoquinone of Formula II into atovaquone of Formula I is prepared by using base sodium hydroxide or potassium hydroxide preferably potassium hydroxide .
The present invention also provides the process wherein using alcoholic solvents like methanol, ethanol, isopropanol preferably methanol.
The present invention provides the process wherein the washing of reaction mass to remove the other organic impurities with organic solvent such as

toluene, dichloromethane and ethyl acetate, preferabley toluene.
The present invention also provides the process wherein the pH of the alkali salt of atovaquone is adjusted by using inorganic acids such as dilute Sulphuric acid or dilute hydrochloric acid to get atovaquone Preferably hydrochloric acid.
The present invention also provides the process wherein the suitable organic solvent for extraction of atovaquone by chlorinated solvent preferably dichloromethane.
In another aspect, the present invention provides the isolation of pure atovaquone by using solvent isopropyl alcohol, acetone, methanol, ethyl acetate and acetonitrile preferably isopropyl alcohol
Atovaquone obtained by the process of present invention is characterized by - X ray powder diffraction pattern peaks at about 7.10., 9.76, 12.79, 20.8 20.77, 21.97, 22.20 and 22.84 ±0.2 degrees and DSC thermogram having a sharp endotherm at 222°C. This polymorphic Form also matches with USP reference standard (Lot No. FOB 190).
BRIEF DESCRIPTION OF THE DRAWING:
FIG.l is a characteristic power X-ray diffraction (bxRD) pattern of atovaquone
prepared according to Example 2(A).
FIG.2 is a characteristic Differential Scanning Calorimetry(DSC) thermogram of
atovaquone prepared according to Example 2(A)
FIG.3 is a characteristic power X-ray diffraction (bxRD) pattern of atovaquone
prepared according to Example 2(B)
FIG.4 is a characteristic Differential Scanning Calorimetry DSC) thermogram of
atovaquone prepared according to Example 2(B)
FIG.5 is a characteristic power X-ray diffraction(FXRD) pattern of atovaquone
prepared according to Example 2(C)
FIG. 6 is a characteristic Differential Scanning Calorimetry (Dgc) thermogram of
atovaquone prepared according to Example 2(C)

FIG.7 is a characteristic power X-ray diffraction(PXRD) pattern of USP reference
standard.
FIG.8 is a characteristic Differential Scanning Calorimetry (DSCj thermogram of
USP reference standard.
EXPERIMENTAL DATA:
Example 1 (A)
Preparation of 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l,4-
naphthoquinone (II)
The mixture of 100 gm of trans-4-(4-chlorophenyl)cyclohexane-l-carboxylic acid, 96.8 gm of 2-chloro-l,4-naphthoquinone and 28.46 gm of silver nitrate was taken in the solution of sulfolane, acetonitrile and water with 1:1 ratio of each. Reaction mixture was heated to reflux. Then a solution of 158.6 gm of ammonium persulfate in water was added to the reaction mixture. After completion of reaction, the mass was cooled to ambient temperature. The mixture of ethyl acetate and cyclohexane with ratio of 1:2 was added and stirred. The solid was filtered at 25-35°C. solid intermediate content trans isomer more than 90% by HPLC purity. Solid was dissolved in dichloromethane and filtered to remove inorganic salts. Filtrate was concentrated completely and isolate solid by cyclohexane to get 38g of Chloro intermediate with the cis isomer less than 5%.
Example 1 (B)
Preparation of 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l,4-
naphthoquinone(II)
The mixture of 100 gm of trans-4-(4-chlorophenyl)cyclohexane-l-carboxylic acid, 96.8 gm of 2-chloro-1,4-naphthoquinone and 28.46 gm of silver nitrate was taken in the solution of sulfolane, acetonitrile and water with 1:1 ratio of each. Reaction mixture was heated to reflux. Then a solution of 158.6 gm of ammonium persulfate in water was added to the reaction mixture. After completion of reaction, the mass was cooled to ambient temperature. The mixture of toluene and cyclohexane with ratio of 1:2 was added and stirred. The solid was filtered at 25-35°C. Solid was dissolved in dichloromethane and filtered to remove inorganic salts. Filtrate was concentrated completely and isolate solid by cyclohexane to get

34g of Chloro intermediate with the cis isomer less than 5%.
Example 1 (C)
Preparation of 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l,4-
naphthoquinone(II)
The mixture of 100 gm of trans-4-(4-chlorophenyl)cyclohexane-l-carboxylic acid, 96.8 gm of 2-chloro-l,4-naphthoquinone and 28.46 gm of silver nitrate was taken in the solution of sulfolane, acetonitrile and water with 1:1 ratio of each. Reaction mixture was heated to reflux. Then a solution of 158.6 gm of ammonium persulfate in water was added to the reaction mixture. After completion of reaction, the mass was cooled to ambient temperature. The mixture of ethyl acetate and cyclohexane with ratio of 1:2 was added and stirred. The solid was filtered at 25-35°C. Solid intermediate content trans isomer more then 90% by HPLC purity. Solid was dissolved in dichloromethane and filtered to remove inorganic salts. Filtrate was concentrated completely and isolate solid by 25% dichloromethane in Methanol to get 32g of Chloro intermediate with the trans
isomre above 98% cis isomer below 1.5% and other single may immunities hel
1%.
Example 1 (D)
Preparation of 2-[4-(4-chlorophenyl)cyclohexyl]-3-chloro-l,4-
naphthoquino ne (II)
The mixture of 100 gm of trans-4-(4-chlorophenyl)cyclohexane-l-carboxylic acid, 96.8 gm of 2-chloro-l,4-naphthoquinone and 28.46 gm of silver nitrate was taken in the solution of sulfolane, acetonitrile and water with 1:1 ratio of each. Reaction mixture was heated to reflux. Then a solution of 158.6 gm of ammonium persulfate in water was added to the reaction mixture. After completion of reaction, the mass was cooled to ambient temperature. The mixture of ethyl acetate and cyclohexane with ratio of 1:2 was added and stirred. The solid was filtered at 25-35°C. solid intermediate content trans isomer more than 90% by HPLC purity. Solid was dissolved in dichloromethane and filtered to remove inorganic salts. Filtrate was concentrated completely and isolate solid by Ethyl acetate to get 35g of Chloro intermediate. Purity by HPLC is above 99% with the cis isomer less than 0.5% and single max below 0.5%. Example 2(A)

Preparation of Atovaquone or 2-[trans-4-(4-Chlorophenyl) cyclohexyl]-3-hydroxy-l,4-naphthoquinone of formula - I
25.0gm (0.0694 moles) of 2-[4-(4-chlorophenyl) cyclohexyl]-3-chloro-l,4-naphthoquinone (obtained form Example-1) in 450 ml of methanol was taken and heated to reflux. A solution of potassium hydroxide 25 gm (0.6250 moles) in 250ml water was added drop-wise in 1-1.5 hrs. Then, reaction mass was refluxed for 1-2 hrs. After completion of reaction, the mass was cooled to 35-40°C. Reaction mass was washed with toluene. Then, dilute HC1 was added to adjust the pH 2-3. Reaction mass was extracted with dichloromethane. The organic layer was concentrated to obtain the crude atovaquone. The crude atovaquone was taken in isopropyl alcohol and heated to reflux , maintained for 1 hr. The reaction mass was then cooled to 25-30°C, filtered, washed with isopropyl alcohol. The product was dried to Yield-84% of pure Atovaquone crystalline form. The obtained Atovaquone from this experiment was characterized by X-ray powder diffraction is shown in Figure 1 and differential scanning calortmetry (DSC) thermogram is shown in Figure 2.
Example 2(B)
Preparation of Atovaquone or 2-[trans-4-(4-Chlorophenyl)cyclohexyl]-3-
hydroxy-l,4-naphthoquinone of formula - I
25.0gm (0.0694 moles) of 2-[4-(4-chlorophenyl) cyclohexyl]-3-chloro-l,4-naphthoquinone (obtained form Example-1) in 450 ml of methanol was taken and heated to reflux. A solution of potassium hydroxide 25 gm (0.6250 moles) in 250ml water was added drop-wise in 1-1.5 hrs. Then, reaction mass was refluxed for 1-2 hrs. After completion of reaction, the mass was cooled to 35-40°C. Reaction mass was washed with toluene. Then, dilute HC1 was added to adjust the pH 2-3. Reaction mass was extracted with dichloromethane. The organic layer was concentrated to obtain the crude atovaquone. The crude atovaquone was taken in acetone and heated to reflux, maintained for 1 hr. The reaction mass was then cooled to 25-30°C, filtered, washed with acetone. The product was dried to Yield- 71% of pure Atovaquone crystalline form. The obtained Atovaquone from this experiment was characterized by X-ray powder diffraction is shown in Figure 3 and differential scanning calorimetry (DSC) thermogram is shown in Figure 4,

Example 2(C)
Preparation of Atovaquone or 2-[trans-4-(4-chlorophenyl)cyclohexyl]-3-
hydroxy-l,4-naphthoquinone of formula - I
25.0gm(0.0694 moles) of 2-[4-(4-chlorophenyl)cyclohexyl]-3-criloro-l,4-naphthoquinone (obtained form Example-1) in 450 ml 0f methanol was taken and heated to reflux. A solution of potassium hydroxide 25 gm (0.6250 moles) in 250ml water was added drop-wise in 1-1.5 hrs. Then reaction mass was reftuxed for 1-2 hrs. After completion of reaction, the mass was cooled to 35-40°C. Reaction mass was washed with toluene. Then,dilute HCl was added to adjust the pH 2-3. Reaction mass was extracted with dichloromethane. The organic layer was concentrated to obtain the crude atovaquone. The atovaquone was taken in acetonitrile and heated to reflux ,maintained for1 hr. The reaction mass was then cooled to 25-30°C, filtered, washed with acetonitrile. The product was dried to Yield-80% of pure Atovaquone crystalline form.the obtained Atovaquone from this experiment was characterized by X-ray powder diffraction is shown in Figure 5 and differential scanning calorimetry (DSC) them orgam is shown in FIgure 6 While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the ihvention is intended to cover all alternatives, modifications and equivalents included within its scope.